diff --git a/newsfragments/6008.changed.md b/newsfragments/6008.changed.md
new file mode 100644
index 00000000000..88acca63f4a
--- /dev/null
+++ b/newsfragments/6008.changed.md
@@ -0,0 +1 @@
+`pyo3-ffi` will now rebuild when the Python virtual environment changes in-place.
diff --git a/pyo3-build-config/src/impl_.rs b/pyo3-build-config/src/impl_.rs
index 3d64cb34e4c..9d6a4666eb5 100644
--- a/pyo3-build-config/src/impl_.rs
+++ b/pyo3-build-config/src/impl_.rs
@@ -1818,10 +1818,16 @@ where
 }
 
 fn venv_interpreter(virtual_env: &OsStr, windows: bool) -> PathBuf {
+    let venv = Path::new(virtual_env);
+    // Rebuild if the virtual environment configuration changes
+    println!(
+        "cargo:rerun-if-changed={}",
+        venv.join("pyvenv.cfg").display()
+    );
     if windows {
-        Path::new(virtual_env).join("Scripts").join("python.exe")
+        venv.join("Scripts").join("python.exe")
     } else {
-        Path::new(virtual_env).join("bin").join("python")
+        venv.join("bin").join("python")
     }
 }