diff --git a/public/app/features/dashboard-scene/panel-edit/PanelDataPane/PanelDataQueriesTab.test.tsx b/public/app/features/dashboard-scene/panel-edit/PanelDataPane/PanelDataQueriesTab.test.tsx
index e3cb5a4f4b1..aad14f4fa8b 100644
--- a/public/app/features/dashboard-scene/panel-edit/PanelDataPane/PanelDataQueriesTab.test.tsx
+++ b/public/app/features/dashboard-scene/panel-edit/PanelDataPane/PanelDataQueriesTab.test.tsx
@@ -175,6 +175,9 @@ const MixedDs = {
     id: 'grafana',
     mixed: true,
   },
+  getRef: () => {
+    return { type: 'datasource', uid: '-- Mixed --' };
+  },
 };
 
 const MixedDsSettingsMock = {
@@ -760,6 +763,67 @@ describe('PanelDataQueriesTab', () => {
         });
       });
     });
+
+    describe('updateDatasourceIfNeeded', () => {
+      it('should update datasource when different datasource reference is provided', async () => {
+        const { queriesTab } = await setupScene('panel-1');
+
+        // Initially should have testdata datasource
+        expect(queriesTab.state.datasource?.uid).toBe('gdev-testdata');
+
+        // Call updateDatasourceIfNeeded with prometheus datasource
+        await queriesTab.updateDatasourceIfNeeded({ uid: 'gdev-prometheus' });
+
+        // Should update to prometheus datasource
+        expect(queriesTab.state.datasource?.uid).toBe('gdev-prometheus');
+        expect(queriesTab.state.dsSettings?.uid).toBe('gdev-prometheus');
+      });
+
+      it('should not update datasource when same datasource reference is provided', async () => {
+        const { queriesTab } = await setupScene('panel-1');
+
+        // Initially should have testdata datasource
+        expect(queriesTab.state.datasource?.uid).toBe('gdev-testdata');
+
+        const originalDatasource = queriesTab.state.datasource;
+        const originalDsSettings = queriesTab.state.dsSettings;
+
+        // Call updateDatasourceIfNeeded with same datasource
+        await queriesTab.updateDatasourceIfNeeded({ uid: 'gdev-testdata' });
+
+        // Should not change the datasource
+        expect(queriesTab.state.datasource).toBe(originalDatasource);
+        expect(queriesTab.state.dsSettings).toBe(originalDsSettings);
+      });
+
+      it('should update datasource to mixed when mixed datasource reference is provided', async () => {
+        const { queriesTab } = await setupScene('panel-1');
+
+        // Initially should have testdata datasource
+        expect(queriesTab.state.datasource?.uid).toBe('gdev-testdata');
+
+        // Call updateDatasourceIfNeeded with mixed datasource
+        await queriesTab.updateDatasourceIfNeeded({ uid: '-- Mixed --' });
+
+        // Should update to mixed datasource
+        expect(queriesTab.state.datasource?.uid).toBe('-- Mixed --');
+        expect(queriesTab.state.dsSettings?.uid).toBe('-- Mixed --');
+      });
+
+      it('should handle case when datasource instance settings are not found', async () => {
+        const { queriesTab } = await setupScene('panel-1');
+
+        // Initially should have testdata datasource
+        expect(queriesTab.state.datasource?.uid).toBe('gdev-testdata');
+
+        // Call updateDatasourceIfNeeded with non-existent datasource
+        await queriesTab.updateDatasourceIfNeeded({ uid: 'non-existent-ds' });
+
+        // Should fall back to default datasource (since mock returns default when not found)
+        expect(queriesTab.state.datasource?.uid).toBe('gdev-testdata');
+        expect(queriesTab.state.dsSettings?.uid).toBe('gdev-testdata');
+      });
+    });
   });
 });
 
diff --git a/public/app/features/dashboard-scene/panel-edit/PanelDataPane/PanelDataQueriesTab.tsx b/public/app/features/dashboard-scene/panel-edit/PanelDataPane/PanelDataQueriesTab.tsx
index d46b7270cb5..9af2af9d11f 100644
--- a/public/app/features/dashboard-scene/panel-edit/PanelDataPane/PanelDataQueriesTab.tsx
+++ b/public/app/features/dashboard-scene/panel-edit/PanelDataPane/PanelDataQueriesTab.tsx
@@ -12,7 +12,7 @@ import {
   SceneObjectState,
   SceneDataQuery,
 } from '@grafana/scenes';
-import { DataQuery } from '@grafana/schema';
+import { DataQuery, DataSourceRef } from '@grafana/schema';
 import { Button, Stack, Tab } from '@grafana/ui';
 import { addQuery } from 'app/core/utils/query';
 import { getLastUsedDatasourceFromStorage } from 'app/features/dashboard/utils/dashboard';
@@ -315,6 +315,21 @@ export class PanelDataQueriesTab extends SceneObjectBase<PanelDataQueriesTabStat
   public get queryRunner(): SceneQueryRunner {
     return getQueryRunnerFor(this.state.panelRef.resolve())!;
   }
+
+  /**
+   * Updates panel datasource when saved queries from different datasources are used.
+   * Handles transition between single and mixed datasource modes.
+   */
+  public updateDatasourceIfNeeded = async (newDatasourceRef: DataSourceRef): Promise<void> => {
+    const { datasource } = this.state;
+    const shouldChangeDatasource = datasource?.uid !== newDatasourceRef.uid;
+    if (shouldChangeDatasource) {
+      const newDatasource = getDatasourceSrv().getInstanceSettings(newDatasourceRef);
+      if (newDatasource) {
+        await this.onChangeDataSource(newDatasource);
+      }
+    }
+  };
 }
 
 export function PanelDataQueriesTabRendered({ model }: SceneComponentProps<PanelDataQueriesTab>) {
@@ -339,6 +354,7 @@ export function PanelDataQueriesTabRendered({ model }: SceneComponentProps<Panel
     );
     const newQueries = addQuery(enrichedQueries, query);
     model.onQueriesChange(newQueries);
+
     if (query.datasource?.uid) {
       const uniqueDatasources = new Set(
         newQueries.map((q) => q.datasource?.uid).filter((uid) => uid !== ExpressionDatasourceUID)
@@ -347,13 +363,7 @@ export function PanelDataQueriesTabRendered({ model }: SceneComponentProps<Panel
       const newDatasourceRef = {
         uid: isMixed ? MIXED_DATASOURCE_NAME : query.datasource.uid,
       };
-      const shouldChangeDatasource = datasource.uid !== newDatasourceRef.uid;
-      if (shouldChangeDatasource) {
-        const newDatasource = getDatasourceSrv().getInstanceSettings(newDatasourceRef);
-        if (newDatasource) {
-          await model.onChangeDataSource(newDatasource);
-        }
-      }
+      await model.updateDatasourceIfNeeded(newDatasourceRef);
     }
   };
 
@@ -376,6 +386,7 @@ export function PanelDataQueriesTabRendered({ model }: SceneComponentProps<Panel
         onAddQuery={model.onAddQuery}
         onQueriesChange={model.onQueriesChange}
         onRunQueries={model.onRunQueries}
+        onUpdateDatasources={queryLibraryEnabled ? model.updateDatasourceIfNeeded : undefined}
         app={CoreApp.PanelEditor}
       />
 
diff --git a/public/app/features/query/components/QueryEditorRows.test.tsx b/public/app/features/query/components/QueryEditorRows.test.tsx
index 220a1a75cf1..c61ec4b15c1 100644
--- a/public/app/features/query/components/QueryEditorRows.test.tsx
+++ b/public/app/features/query/components/QueryEditorRows.test.tsx
@@ -87,6 +87,117 @@ describe('QueryEditorRows', () => {
     );
   });
 
+  it('Should call onUpdateDatasources when replacing query with different datasource creates mixed scenario', () => {
+    const onQueriesChangeMock = jest.fn();
+    const onUpdateDatasourcesMock = jest.fn();
+
+    const testProps = {
+      ...props,
+      onQueriesChange: onQueriesChangeMock,
+      onUpdateDatasources: onUpdateDatasourcesMock,
+      dsSettings: { ...props.dsSettings, uid: 'current-datasource' },
+      queries: [
+        { datasource: { uid: 'current-datasource', type: 'alertmanager' }, refId: 'A' },
+        { datasource: { uid: 'current-datasource', type: 'alertmanager' }, refId: 'B' },
+      ],
+    };
+
+    const component = new QueryEditorRows(testProps);
+    const replacementQuery = {
+      refId: 'A',
+      datasource: { uid: 'different-datasource', type: 'prometheus' },
+      expr: 'new query content',
+    };
+
+    component.onReplaceQuery(replacementQuery, 0);
+
+    expect(onUpdateDatasourcesMock).toHaveBeenCalledWith({
+      uid: MIXED_DATASOURCE_NAME,
+    });
+  });
+
+  it('Should call onUpdateDatasources when replacing query results in single different datasource', () => {
+    const onQueriesChangeMock = jest.fn();
+    const onUpdateDatasourcesMock = jest.fn();
+
+    const testProps = {
+      ...props,
+      onQueriesChange: onQueriesChangeMock,
+      onUpdateDatasources: onUpdateDatasourcesMock,
+      dsSettings: { ...props.dsSettings, uid: 'current-datasource' },
+      queries: [{ datasource: { uid: 'current-datasource', type: 'alertmanager' }, refId: 'A' }],
+    };
+
+    const component = new QueryEditorRows(testProps);
+    const replacementQuery = {
+      refId: 'A',
+      datasource: { uid: 'different-datasource', type: 'prometheus' },
+      expr: 'new query content',
+    };
+
+    component.onReplaceQuery(replacementQuery, 0);
+
+    expect(onUpdateDatasourcesMock).toHaveBeenCalledWith({
+      uid: 'different-datasource',
+    });
+  });
+
+  it('Should not call onUpdateDatasources when replacing query with same datasource', () => {
+    const onQueriesChangeMock = jest.fn();
+    const onUpdateDatasourcesMock = jest.fn();
+
+    const testProps = {
+      ...props,
+      onQueriesChange: onQueriesChangeMock,
+      onUpdateDatasources: onUpdateDatasourcesMock,
+      dsSettings: { ...props.dsSettings, uid: 'same-datasource' },
+      queries: [
+        { datasource: { uid: 'same-datasource', type: 'prometheus' }, refId: 'A' },
+        { datasource: { uid: 'same-datasource', type: 'prometheus' }, refId: 'B' },
+      ],
+    };
+
+    const component = new QueryEditorRows(testProps);
+    const replacementQuery = {
+      refId: 'A',
+      datasource: { uid: 'same-datasource', type: 'prometheus' },
+      expr: 'new query content',
+    };
+
+    component.onReplaceQuery(replacementQuery, 0);
+
+    expect(onUpdateDatasourcesMock).not.toHaveBeenCalled();
+  });
+
+  it('Should call onUpdateDatasources with mixed datasource when replacing creates mixed scenario', () => {
+    const onQueriesChangeMock = jest.fn();
+    const onUpdateDatasourcesMock = jest.fn();
+
+    const testProps = {
+      ...props,
+      onQueriesChange: onQueriesChangeMock,
+      onUpdateDatasources: onUpdateDatasourcesMock,
+      dsSettings: { ...props.dsSettings, uid: 'current-datasource' },
+      queries: [
+        { datasource: { uid: 'datasource-1', type: 'loki' }, refId: 'A' },
+        { datasource: { uid: 'datasource-2', type: 'test-data' }, refId: 'B' },
+      ],
+    };
+
+    const component = new QueryEditorRows(testProps);
+    const replacementQuery = {
+      refId: 'A',
+      datasource: { uid: 'datasource-3', type: 'prometheus' },
+      expr: 'new query content',
+    };
+
+    component.onReplaceQuery(replacementQuery, 0);
+
+    expect(onUpdateDatasourcesMock).toHaveBeenCalledWith({
+      uid: MIXED_DATASOURCE_NAME,
+    });
+  });
+
   it('Should render queries', async () => {
     const {
       renderResult: { rerender },