diff --git a/packages/calcite-components/src/components/popover/PopoverManager.ts b/packages/calcite-components/src/components/popover/PopoverManager.ts
index 00f3cda446e..b872f75af11 100644
--- a/packages/calcite-components/src/components/popover/PopoverManager.ts
+++ b/packages/calcite-components/src/components/popover/PopoverManager.ts
@@ -87,7 +87,7 @@ export default class PopoverManager {
   };
 
   private clickHandler = (event: PointerEvent): void => {
-    if (isKeyboardTriggeredClick(event)) {
+    if (isKeyboardTriggeredClick(event) || event.defaultPrevented) {
       return;
     }
 
diff --git a/packages/calcite-components/src/components/popover/popover.e2e.ts b/packages/calcite-components/src/components/popover/popover.e2e.ts
index 14568e116ea..ab7c8425a08 100644
--- a/packages/calcite-components/src/components/popover/popover.e2e.ts
+++ b/packages/calcite-components/src/components/popover/popover.e2e.ts
@@ -368,6 +368,35 @@ describe("calcite-popover", () => {
     expect(await popover.getProperty("open")).toBe(true);
   });
 
+  it("should not open popovers if event is prevented", async () => {
+    const page = await newE2EPage();
+
+    await page.setContent(html`
+      <calcite-popover reference-element="ref">Content</calcite-popover>
+      <div id="ref">Button</div>
+    `);
+
+    await page.waitForChanges();
+
+    const popover = await page.find("calcite-popover");
+
+    expect(await popover.getProperty("open")).toBe(false);
+
+    await page.$eval("#ref", (ref) => {
+      ref.addEventListener("click", (event) => {
+        event.preventDefault();
+      });
+    });
+
+    const referenceElement = await page.find("#ref");
+
+    await referenceElement.click();
+
+    await page.waitForChanges();
+
+    expect(await popover.getProperty("open")).toBe(false);
+  });
+
   it("should not be visible if reference is hidden", async () => {
     const page = await newE2EPage();
 
diff --git a/packages/calcite-components/src/components/tooltip/TooltipManager.ts b/packages/calcite-components/src/components/tooltip/TooltipManager.ts
index 1c5539ac0be..2f5f68ee73d 100644
--- a/packages/calcite-components/src/components/tooltip/TooltipManager.ts
+++ b/packages/calcite-components/src/components/tooltip/TooltipManager.ts
@@ -97,6 +97,10 @@ export default class TooltipManager {
   };
 
   private pointerMoveHandler = (event: PointerEvent): void => {
+    if (event.defaultPrevented) {
+      return;
+    }
+
     const composedPath = event.composedPath();
     const { activeTooltip } = this;
 
@@ -129,6 +133,10 @@ export default class TooltipManager {
   }
 
   private clickHandler = (event: Event): void => {
+    if (event.defaultPrevented) {
+      return;
+    }
+
     this.clickedTooltip = null;
     const composedPath = event.composedPath();
     const tooltip = this.queryTooltip(composedPath);
@@ -160,6 +168,10 @@ export default class TooltipManager {
   };
 
   private focusInHandler = (event: FocusEvent): void => {
+    if (event.defaultPrevented) {
+      return;
+    }
+
     const composedPath = event.composedPath();
     const tooltip = this.queryTooltip(composedPath);
 
diff --git a/packages/calcite-components/src/components/tooltip/tooltip.e2e.ts b/packages/calcite-components/src/components/tooltip/tooltip.e2e.ts
index db017596b8d..99db9e68c6c 100644
--- a/packages/calcite-components/src/components/tooltip/tooltip.e2e.ts
+++ b/packages/calcite-components/src/components/tooltip/tooltip.e2e.ts
@@ -320,6 +320,34 @@ describe("calcite-tooltip", () => {
     expect(await positionContainer.isVisible()).toBe(true);
   });
 
+  it("should not open when hover event is prevented", async () => {
+    const page = await newE2EPage();
+
+    await page.setContent(
+      `<calcite-tooltip reference-element="ref">content</calcite-tooltip><div id="ref">referenceElement</div>`,
+    );
+
+    await page.waitForChanges();
+
+    const positionContainer = await page.find(`calcite-tooltip >>> .${CSS.positionContainer}`);
+
+    expect(await positionContainer.isVisible()).toBe(false);
+
+    await page.$eval("#ref", (ref) => {
+      ref.addEventListener("pointermove", (event) => {
+        event.preventDefault();
+      });
+    });
+
+    const ref = await page.find("#ref");
+
+    await ref.hover();
+
+    await page.waitForTimeout(TOOLTIP_OPEN_DELAY_MS);
+
+    expect(await positionContainer.isVisible()).toBe(false);
+  });
+
   it("should honor hover interaction with span inside", async () => {
     const page = await newE2EPage();
 
@@ -426,6 +454,34 @@ describe("calcite-tooltip", () => {
     expect(await tooltip.getProperty("open")).toBe(false);
   });
 
+  it("should not open if focus event is prevented", async () => {
+    const page = await newE2EPage();
+
+    await page.setContent(html`
+      <button id="test">test</button>
+      <calcite-tooltip reference-element="ref">Content</calcite-tooltip>
+      <button id="ref">Button</button>
+    `);
+
+    await page.waitForChanges();
+
+    const tooltip = await page.find("calcite-tooltip");
+
+    expect(await tooltip.getProperty("open")).toBe(false);
+
+    await page.$eval("#ref", (ref) => {
+      ref.addEventListener("focusin", (event) => {
+        event.preventDefault();
+      });
+
+      ref.dispatchEvent(new FocusEvent("focusin", { bubbles: true, cancelable: true }));
+    });
+
+    await page.waitForChanges();
+
+    expect(await tooltip.getProperty("open")).toBe(false);
+  });
+
   it("should handle mouse events", async () => {
     const page = await newE2EPage();
 
@@ -547,6 +603,45 @@ describe("calcite-tooltip", () => {
     await assertEscapeKeyCanceled(page, true);
   });
 
+  it("should not close with ESC key if event is prevented", async () => {
+    const page = await newE2EPage();
+
+    await page.setContent(html`
+      <calcite-tooltip reference-element="ref">Content</calcite-tooltip>
+      <button id="ref">Button</button>
+    `);
+
+    await page.waitForChanges();
+
+    const tooltip = await page.find("calcite-tooltip");
+
+    expect(await tooltip.getProperty("open")).toBe(false);
+
+    const referenceElement = await page.find("#ref");
+
+    await referenceElement.focus();
+
+    await referenceElement.hover();
+
+    await page.waitForTimeout(TOOLTIP_OPEN_DELAY_MS);
+
+    await page.waitForChanges();
+
+    expect(await tooltip.getProperty("open")).toBe(true);
+
+    await page.evaluate(() => {
+      document.body.addEventListener("keydown", (event) => {
+        if (event.key === "Escape") {
+          event.preventDefault();
+        }
+      });
+    });
+
+    await dispatchKeydownEvent(page, "#ref", "Escape");
+
+    expect(await tooltip.getProperty("open")).toBe(true);
+  });
+
   it("should only open the last focused tooltip", async () => {
     const page = await newE2EPage();
 
@@ -1175,6 +1270,25 @@ describe("calcite-tooltip", () => {
       expect(await tooltip.getProperty("open")).toBe(false);
     });
 
+    it("should not open when click event is prevented", async () => {
+      const page = await newE2EPage();
+      await page.setContent(pageContent);
+      await skipAnimations(page);
+      await page.waitForChanges();
+      const tooltip = await page.find("calcite-tooltip");
+
+      await page.$eval("#ref", (ref) => {
+        ref.addEventListener("click", (event) => {
+          event.preventDefault();
+        });
+
+        ref.dispatchEvent(new MouseEvent("click", { bubbles: true, cancelable: true }));
+      });
+
+      await page.waitForChanges();
+      expect(await tooltip.getProperty("open")).toBe(false);
+    });
+
     it("should work when focusing on a reference element first", async () => {
       const page = await newE2EPage();
       await page.setContent(pageContent);