diff --git a/.changeset/tame-foxes-tan.md b/.changeset/tame-foxes-tan.md
new file mode 100644
index 00000000000..f70d046cf7d
--- /dev/null
+++ b/.changeset/tame-foxes-tan.md
@@ -0,0 +1,5 @@
+---
+"@primer/react": patch
+---
+
+Fix `MarkdownEditor` file uploads inserting the URL into the wrong input when an overlay is open
diff --git a/src/drafts/hooks/useSyntheticChange.ts b/src/drafts/hooks/useSyntheticChange.ts
index cf1c3809c0b..e67c3617bf1 100644
--- a/src/drafts/hooks/useSyntheticChange.ts
+++ b/src/drafts/hooks/useSyntheticChange.ts
@@ -94,7 +94,7 @@ export const useSyntheticChange = ({inputRef, fallbackEventHandler}: UseSyntheti
       const input = inputRef.current
       if (!input) return
 
-      input.focus() // the input must be focused to execute execCommand
+      input.focus()
 
       const replaceRange = replaceRange_ ?? [
         input.selectionStart ?? input.value.length,
@@ -113,6 +113,10 @@ export const useSyntheticChange = ({inputRef, fallbackEventHandler}: UseSyntheti
       // but it's a deprecated API and there's no alternative. It also doesn't work in test environments
       let execCommandResult = false
       try {
+        // There is no guarantee the input is focused even after calling `focus()` on it. For example, the focus could
+        // be trapped by an overlay. In that case we must prevent the change from happening in some unexpected target.
+        if (document.activeElement !== input) throw new Error('Input must be focused to use execCommand')
+
         // expand selection to the whole range and replace it with the new value
         input.setSelectionRange(replaceRange[0], replaceRange[1])
         execCommandResult =