diff --git a/.changes/next-release/bugfix-AmazonS3-3b61c48.json b/.changes/next-release/bugfix-AmazonS3-3b61c48.json
new file mode 100644
index 000000000000..2d769593c561
--- /dev/null
+++ b/.changes/next-release/bugfix-AmazonS3-3b61c48.json
@@ -0,0 +1,6 @@
+{
+    "category": "Amazon S3", 
+    "contributor": "", 
+    "type": "bugfix", 
+    "description": "Fixed an issue that resulted in a NullPointerException when an invalid or global region was used on an S3 client. Fixes [#2885](https://github.com/aws/aws-sdk-java-v2/issues/2885)."
+}
diff --git a/services/s3/src/it/java/software/amazon/awssdk/services/s3/ListBucketsIntegrationTest.java b/services/s3/src/it/java/software/amazon/awssdk/services/s3/ListBucketsIntegrationTest.java
new file mode 100644
index 000000000000..6bc78b9fce93
--- /dev/null
+++ b/services/s3/src/it/java/software/amazon/awssdk/services/s3/ListBucketsIntegrationTest.java
@@ -0,0 +1,28 @@
+/*
+ * Copyright Amazon.com, Inc. or its affiliates. All Rights Reserved.
+ *
+ * Licensed under the Apache License, Version 2.0 (the "License").
+ * You may not use this file except in compliance with the License.
+ * A copy of the License is located at
+ *
+ *  http://aws.amazon.com/apache2.0
+ *
+ * or in the "license" file accompanying this file. This file is distributed
+ * on an "AS IS" BASIS, WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either
+ * express or implied. See the License for the specific language governing
+ * permissions and limitations under the License.
+ */
+
+package software.amazon.awssdk.services.s3;
+
+import org.junit.Test;
+import software.amazon.awssdk.regions.Region;
+
+public class ListBucketsIntegrationTest extends S3IntegrationTestBase {
+    @Test
+    public void listBuckets_InGlobal_DoesNotThrowException() {
+        try (S3Client s3 = s3ClientBuilder().region(Region.AWS_GLOBAL).build()) {
+            s3.listBuckets();
+        }
+    }
+}
diff --git a/services/s3/src/main/java/software/amazon/awssdk/services/s3/internal/endpoints/S3BucketEndpointResolver.java b/services/s3/src/main/java/software/amazon/awssdk/services/s3/internal/endpoints/S3BucketEndpointResolver.java
index ea11e64b5395..fc1612d75cdf 100644
--- a/services/s3/src/main/java/software/amazon/awssdk/services/s3/internal/endpoints/S3BucketEndpointResolver.java
+++ b/services/s3/src/main/java/software/amazon/awssdk/services/s3/internal/endpoints/S3BucketEndpointResolver.java
@@ -26,6 +26,7 @@
 import java.net.URI;
 import software.amazon.awssdk.annotations.SdkInternalApi;
 import software.amazon.awssdk.http.SdkHttpRequest;
+import software.amazon.awssdk.regions.PartitionMetadata;
 import software.amazon.awssdk.regions.RegionMetadata;
 import software.amazon.awssdk.services.s3.S3Configuration;
 import software.amazon.awssdk.services.s3.internal.BucketUtils;
@@ -69,7 +70,10 @@ public ConfiguredS3SdkHttpRequest applyEndpointConfiguration(S3EndpointResolverC
     private static URI resolveEndpoint(S3EndpointResolverContext context) {
         SdkHttpRequest request = context.request();
         String protocol = request.protocol();
-        String dnsSuffixWithoutTagConsideration = RegionMetadata.of(context.region()).domain();
+        RegionMetadata regionMetadata = RegionMetadata.of(context.region());
+        String dnsSuffixWithoutTagConsideration = regionMetadata != null ?
+                                                  regionMetadata.domain() :
+                                                  PartitionMetadata.of(context.region()).dnsSuffix();
         S3Configuration serviceConfiguration = context.serviceConfiguration();
 
         boolean useAccelerate = isAccelerateEnabled(serviceConfiguration) && isAccelerateSupported(context.originalRequest());
diff --git a/services/s3/src/test/java/software/amazon/awssdk/services/s3/InvalidRegionTest.java b/services/s3/src/test/java/software/amazon/awssdk/services/s3/InvalidRegionTest.java
index 467f949301dd..029d6ef6c5d0 100644
--- a/services/s3/src/test/java/software/amazon/awssdk/services/s3/InvalidRegionTest.java
+++ b/services/s3/src/test/java/software/amazon/awssdk/services/s3/InvalidRegionTest.java
@@ -22,6 +22,7 @@
 import software.amazon.awssdk.auth.credentials.AnonymousCredentialsProvider;
 import software.amazon.awssdk.core.exception.SdkClientException;
 import software.amazon.awssdk.regions.Region;
+import software.amazon.awssdk.services.s3.model.HeadBucketRequest;
 import software.amazon.awssdk.services.s3.presigner.S3Presigner;
 
 public class InvalidRegionTest {
@@ -47,6 +48,17 @@ public void invalidS3UtilitiesRegionAtRequestGivesHelpfulMessage() {
             .hasMessageContaining("us-west-2");
     }
 
+    @Test
+    public void nonExistentRegionGivesHelpfulMessage() {
+        S3Client s3Client = S3Client.builder()
+                                    .region(Region.of("does-not-exist"))
+                                    .credentialsProvider(AnonymousCredentialsProvider.create())
+                                    .build();
+        assertThatThrownBy(() -> s3Client.headBucket(HeadBucketRequest.builder().bucket("myBucket").build()))
+            .isInstanceOf(SdkClientException.class)
+            .hasMessageContaining("UnknownHostException");
+    }
+
     @Test
     public void invalidS3ArnRegionAtRequestGivesHelpfulMessage() {
         S3Client client = S3Client.builder()