diff --git a/.changes/next-release/enhancement-Endpoints-18366.json b/.changes/next-release/enhancement-Endpoints-18366.json
new file mode 100644
index 0000000000..224c76fb35
--- /dev/null
+++ b/.changes/next-release/enhancement-Endpoints-18366.json
@@ -0,0 +1,5 @@
+{
+  "type": "enhancement",
+  "category": "Endpoints",
+  "description": "Improve the NoRegionError message to explain how to set a region (region_name, AWS_DEFAULT_REGION, or ~/.aws/config)."
+}
diff --git a/botocore/exceptions.py b/botocore/exceptions.py
index 294bbf4020..fee4a968f9 100644
--- a/botocore/exceptions.py
+++ b/botocore/exceptions.py
@@ -243,7 +243,11 @@ class BaseEndpointResolverError(BotoCoreError):
 class NoRegionError(BaseEndpointResolverError):
     """No region was specified."""
 
-    fmt = 'You must specify a region.'
+    fmt = (
+        'You must specify a region. This can be done by passing the region_name '
+        'argument to the client or session, using the AWS_DEFAULT_REGION '
+        'environment variable, or setting "region" in the aws config file.'
+    )
 
 
 class EndpointVariantError(BaseEndpointResolverError):