diff --git a/.changelog/4943.fixed b/.changelog/4943.fixed
new file mode 100644
index 0000000000..9f5cf38c26
--- /dev/null
+++ b/.changelog/4943.fixed
@@ -0,0 +1 @@
+`opentelemetry-instrumentation-sqlalchemy`: avoid `IndexError` in `_operation_name` for comment-only or whitespace-only statements
diff --git a/instrumentation/opentelemetry-instrumentation-sqlalchemy/src/opentelemetry/instrumentation/sqlalchemy/engine.py b/instrumentation/opentelemetry-instrumentation-sqlalchemy/src/opentelemetry/instrumentation/sqlalchemy/engine.py
index 3185422b47..67ce599071 100644
--- a/instrumentation/opentelemetry-instrumentation-sqlalchemy/src/opentelemetry/instrumentation/sqlalchemy/engine.py
+++ b/instrumentation/opentelemetry-instrumentation-sqlalchemy/src/opentelemetry/instrumentation/sqlalchemy/engine.py
@@ -315,8 +315,12 @@ def _operation_name(self, db_name, statement):
             # use cases and uses the SQL statement in span name correctly as per the spec.
             # For some very special cases it might not record the correct statement if the SQL
             # dialect is too weird but in any case it shouldn't break anything.
-            # Strip leading comments so we get the operation name.
-            parts.append(self._leading_comment_remover.sub("", statement).split()[0])
+            # Strip leading comments so we get the operation name. A statement that
+            # is truthy but has no tokens left (comment-only or whitespace-only) must
+            # not raise IndexError; skip adding an operation part in that case.
+            tokens = self._leading_comment_remover.sub("", statement).split()
+            if tokens:
+                parts.append(tokens[0])
         if db_name:
             parts.append(db_name)
         if not parts:
diff --git a/instrumentation/opentelemetry-instrumentation-sqlalchemy/tests/test_sqlalchemy.py b/instrumentation/opentelemetry-instrumentation-sqlalchemy/tests/test_sqlalchemy.py
index 023df92101..969750e001 100644
--- a/instrumentation/opentelemetry-instrumentation-sqlalchemy/tests/test_sqlalchemy.py
+++ b/instrumentation/opentelemetry-instrumentation-sqlalchemy/tests/test_sqlalchemy.py
@@ -59,6 +59,20 @@ def tearDown(self):
         super().tearDown()
         SQLAlchemyInstrumentor().uninstrument()
 
+    def test_operation_name_comment_or_whitespace_only(self):
+        # Regression: a comment-only or whitespace-only statement is truthy but has
+        # no tokens after leading-comment stripping; _operation_name must not raise
+        # IndexError and should fall back to the db name / vendor.
+        engine = create_engine("sqlite:///:memory:")
+        tracer = self.tracer_provider.get_tracer(__name__)
+        engine_tracer = EngineTracer(tracer, engine, mock.Mock())
+        self.assertEqual(
+            engine_tracer._operation_name("mydb", "/* comment only */"), "mydb"
+        )
+        self.assertEqual(
+            engine_tracer._operation_name(None, "   "), engine_tracer.vendor
+        )
+
     def test_trace_integration(self):
         engine = create_engine("sqlite:///:memory:")
         SQLAlchemyInstrumentor().instrument(