diff --git a/hbase-client/src/main/java/org/apache/hadoop/hbase/client/AsyncNonMetaRegionLocator.java b/hbase-client/src/main/java/org/apache/hadoop/hbase/client/AsyncNonMetaRegionLocator.java
index 9246adbe986..7f25708df2e 100644
--- a/hbase-client/src/main/java/org/apache/hadoop/hbase/client/AsyncNonMetaRegionLocator.java
+++ b/hbase-client/src/main/java/org/apache/hadoop/hbase/client/AsyncNonMetaRegionLocator.java
@@ -17,6 +17,7 @@
  */
 package org.apache.hadoop.hbase.client;
 
+import static org.apache.hadoop.hbase.HConstants.EMPTY_END_ROW;
 import static org.apache.hadoop.hbase.HConstants.NINES;
 import static org.apache.hadoop.hbase.HConstants.ZEROES;
 import static org.apache.hadoop.hbase.TableName.META_TABLE_NAME;
@@ -169,9 +170,10 @@ class AsyncNonMetaRegionLocator {
         // startKey < req.row and endKey >= req.row. Here we split it to endKey == req.row ||
         // (endKey > req.row && startKey < req.row). The two conditions are equal since startKey <
         // endKey.
-        int c = Bytes.compareTo(loc.getRegion().getEndKey(), req.row);
-        completed =
-          c == 0 || (c > 0 && Bytes.compareTo(loc.getRegion().getStartKey(), req.row) < 0);
+        byte[] endKey = loc.getRegion().getEndKey();
+        int c = Bytes.compareTo(endKey, req.row);
+        completed = c == 0 || ((c > 0 || Bytes.equals(EMPTY_END_ROW, endKey)) &&
+          Bytes.compareTo(loc.getRegion().getStartKey(), req.row) < 0);
       } else {
         completed = loc.getRegion().containsRow(req.row);
       }
diff --git a/hbase-server/src/test/java/org/apache/hadoop/hbase/client/TestAsyncNonMetaRegionLocator.java b/hbase-server/src/test/java/org/apache/hadoop/hbase/client/TestAsyncNonMetaRegionLocator.java
index eeaf99f9ec6..cb09b79240a 100644
--- a/hbase-server/src/test/java/org/apache/hadoop/hbase/client/TestAsyncNonMetaRegionLocator.java
+++ b/hbase-server/src/test/java/org/apache/hadoop/hbase/client/TestAsyncNonMetaRegionLocator.java
@@ -389,4 +389,15 @@ public class TestAsyncNonMetaRegionLocator {
       }
     });
   }
+
+  // Testcase for HBASE-21961
+  @Test
+  public void testLocateBeforeInOnlyRegion() throws IOException, InterruptedException {
+    createSingleRegionTable();
+    HRegionLocation loc =
+      getDefaultRegionLocation(TABLE_NAME, Bytes.toBytes(1), RegionLocateType.BEFORE, false).join();
+    // should locate to the only region
+    assertArrayEquals(loc.getRegion().getStartKey(), EMPTY_START_ROW);
+    assertArrayEquals(loc.getRegion().getEndKey(), EMPTY_END_ROW);
+  }
 }