diff --git a/src/cdk/overlay/overlay.ts b/src/cdk/overlay/overlay.ts
index 6584da581763..c82136f254fe 100644
--- a/src/cdk/overlay/overlay.ts
+++ b/src/cdk/overlay/overlay.ts
@@ -68,7 +68,10 @@ export function createOverlayRef(injector: Injector, config?: OverlayConfig): Ov
 
   overlayConfig.direction = overlayConfig.direction || directionality.value;
 
-  if (!('showPopover' in doc.body)) {
+  // `document.body` can be null during page navigation or unload cycles per the WHATWG spec
+  // (https://html.spec.whatwg.org/multipage/dom.html#dom-document-body), even though TypeScript
+  // types it as non-nullable. Guard against it to avoid "Cannot use 'in' operator ... in null".
+  if (!doc.body || !('showPopover' in doc.body)) {
     overlayConfig.usePopover = false;
   } else {
     overlayConfig.usePopover = config?.usePopover ?? defaultUsePopover;