diff --git a/core/src/components/item/item.tsx b/core/src/components/item/item.tsx
index 6384927de80..e5269bb4f0b 100644
--- a/core/src/components/item/item.tsx
+++ b/core/src/components/item/item.tsx
@@ -37,6 +37,7 @@ export class Item implements ComponentInterface, AnchorInterface, ButtonInterfac
 
   @State() multipleInputs = false;
   @State() focusable = true;
+  @State() isInteractive = false;
 
   /**
    * The color to use from your application's color palette.
@@ -172,14 +173,12 @@ export class Item implements ComponentInterface, AnchorInterface, ButtonInterfac
   componentDidLoad() {
     raf(() => {
       this.setMultipleInputs();
+      this.setIsInteractive();
       this.focusable = this.isFocusable();
     });
   }
 
-  // If the item contains multiple clickable elements and/or inputs, then the item
-  // should not have a clickable input cover over the entire item to prevent
-  // interfering with their individual click events
-  private setMultipleInputs() {
+  private totalNestedInputs() {
     // The following elements have a clickable cover that is relative to the entire item
     const covers = this.el.querySelectorAll('ion-checkbox, ion-datetime, ion-select, ion-radio');
 
@@ -193,6 +192,19 @@ export class Item implements ComponentInterface, AnchorInterface, ButtonInterfac
     // The following elements should also stay clickable when an input with cover is present
     const clickables = this.el.querySelectorAll('ion-router-link, ion-button, a, button');
 
+    return {
+      covers,
+      inputs,
+      clickables,
+    };
+  }
+
+  // If the item contains multiple clickable elements and/or inputs, then the item
+  // should not have a clickable input cover over the entire item to prevent
+  // interfering with their individual click events
+  private setMultipleInputs() {
+    const { covers, inputs, clickables } = this.totalNestedInputs();
+
     // Check for multiple inputs to change the position of the input cover to relative
     // for all of the covered inputs above
     this.multipleInputs =
@@ -201,6 +213,19 @@ export class Item implements ComponentInterface, AnchorInterface, ButtonInterfac
       (covers.length > 0 && this.isClickable());
   }
 
+  private setIsInteractive() {
+    // If item contains any interactive children, set isInteractive to `true`
+    const { covers, inputs, clickables } = this.totalNestedInputs();
+
+    this.isInteractive = covers.length > 0 || inputs.length > 0 || clickables.length > 0;
+  }
+
+  // slot change listener updates state to reflect how/if item should be interactive
+  private updateInteractivityOnSlotChange = () => {
+    this.setIsInteractive();
+    this.setMultipleInputs();
+  };
+
   // If the item contains an input including a checkbox, datetime, select, or radio
   // then the item will have a clickable input cover that covers the item
   // that should get the hover, focused and activated states UNLESS it has multiple
@@ -364,12 +389,12 @@ export class Item implements ComponentInterface, AnchorInterface, ButtonInterfac
           disabled={disabled}
           {...clickFn}
         >
-          <slot name="start"></slot>
+          <slot name="start" onSlotchange={this.updateInteractivityOnSlotChange}></slot>
           <div class="item-inner">
             <div class="input-wrapper">
-              <slot></slot>
+              <slot onSlotchange={this.updateInteractivityOnSlotChange}></slot>
             </div>
-            <slot name="end"></slot>
+            <slot name="end" onSlotchange={this.updateInteractivityOnSlotChange}></slot>
             {showDetail && (
               <ion-icon
                 icon={detailIcon}
diff --git a/core/src/components/item/test/inputs/item.e2e.ts b/core/src/components/item/test/inputs/item.e2e.ts
index 27ca3149b91..29685e87521 100644
--- a/core/src/components/item/test/inputs/item.e2e.ts
+++ b/core/src/components/item/test/inputs/item.e2e.ts
@@ -252,5 +252,46 @@ configs({ directions: ['ltr'] }).forEach(({ title, screenshot, config }) => {
 
       await expect(list).toHaveScreenshot(screenshot(`item-inputs-div-with-inputs`));
     });
+
+    test('should update interactivity state when elements are conditionally rendered', async ({ page }, testInfo) => {
+      testInfo.annotations.push({
+        type: 'issue',
+        description: 'https://github.com/ionic-team/ionic-framework/issues/29763',
+      });
+
+      await page.setContent(
+        `
+        <ion-list>
+          <ion-item>
+            <ion-label>Conditional Checkbox</ion-label>
+          </ion-item>
+        </ion-list>
+        `,
+        config
+      );
+
+      const item = page.locator('ion-item');
+
+      await page.evaluate(() => {
+        const item = document.querySelector('ion-item');
+        const checkbox = document.createElement('ion-checkbox');
+        item?.appendChild(checkbox);
+      });
+
+      await page.waitForChanges();
+
+      const checkbox = page.locator('ion-checkbox');
+      await expect(checkbox).not.toBeChecked();
+
+      // Test that clicking on the left edge of the item toggles the checkbox
+      await item.click({
+        position: {
+          x: 5,
+          y: 5,
+        },
+      });
+
+      await expect(checkbox).toBeChecked();
+    });
   });
 });