diff --git a/doc/source/whatsnew/v1.4.1.rst b/doc/source/whatsnew/v1.4.1.rst
index 9509b96055255..ec4a1b7348262 100644
--- a/doc/source/whatsnew/v1.4.1.rst
+++ b/doc/source/whatsnew/v1.4.1.rst
@@ -20,7 +20,8 @@ Fixed regressions
 - Regression in :meth:`DataFrame.iat` setting values leading to not propagating correctly in subsequent lookups (:issue:`45684`)
 - Regression in :meth:`DataFrame.loc.__setitem__` losing :class:`Index` name if :class:`DataFrame` was empty before (:issue:`45621`)
 - Regression in :func:`join` with overlapping :class:`IntervalIndex` raising an ``InvalidIndexError`` (:issue:`45661`)
-
+- Regression in :func:`read_sql` with a DBAPI2 connection that is not an instance of ``sqlite3.Connection`` incorrectly requiring SQLAlchemy be installed (:issue:`45660`)
+-
 
 .. ---------------------------------------------------------------------------
 
diff --git a/pandas/io/sql.py b/pandas/io/sql.py
index fcb3f5177ae3f..ba18412856d6c 100644
--- a/pandas/io/sql.py
+++ b/pandas/io/sql.py
@@ -736,12 +736,15 @@ def pandasSQL_builder(con, schema: str | None = None):
     if isinstance(con, sqlite3.Connection) or con is None:
         return SQLiteDatabase(con)
 
-    sqlalchemy = import_optional_dependency("sqlalchemy")
+    sqlalchemy = import_optional_dependency("sqlalchemy", errors="ignore")
 
     if isinstance(con, str):
-        con = sqlalchemy.create_engine(con)
+        if sqlalchemy is None:
+            raise ImportError("Using URI string without sqlalchemy installed.")
+        else:
+            con = sqlalchemy.create_engine(con)
 
-    if isinstance(con, sqlalchemy.engine.Connectable):
+    if sqlalchemy is not None and isinstance(con, sqlalchemy.engine.Connectable):
         return SQLDatabase(con, schema=schema)
 
     warnings.warn(
diff --git a/pandas/tests/io/test_sql.py b/pandas/tests/io/test_sql.py
index 584308db3bae8..e383617c020aa 100644
--- a/pandas/tests/io/test_sql.py
+++ b/pandas/tests/io/test_sql.py
@@ -1532,9 +1532,25 @@ def test_sql_open_close(self, test_frame3):
     @pytest.mark.skipif(SQLALCHEMY_INSTALLED, reason="SQLAlchemy is installed")
     def test_con_string_import_error(self):
         conn = "mysql://root@localhost/pandas"
-        with pytest.raises(ImportError, match="SQLAlchemy"):
+        msg = "Using URI string without sqlalchemy installed"
+        with pytest.raises(ImportError, match=msg):
             sql.read_sql("SELECT * FROM iris", conn)
 
+    @pytest.mark.skipif(SQLALCHEMY_INSTALLED, reason="SQLAlchemy is installed")
+    def test_con_unknown_dbapi2_class_does_not_error_without_sql_alchemy_installed(
+        self,
+    ):
+        class MockSqliteConnection:
+            def __init__(self, *args, **kwargs):
+                self.conn = sqlite3.Connection(*args, **kwargs)
+
+            def __getattr__(self, name):
+                return getattr(self.conn, name)
+
+        conn = MockSqliteConnection(":memory:")
+        with tm.assert_produces_warning(UserWarning):
+            sql.read_sql("SELECT 1", conn)
+
     def test_read_sql_delegate(self):
         iris_frame1 = sql.read_sql_query("SELECT * FROM iris", self.conn)
         iris_frame2 = sql.read_sql("SELECT * FROM iris", self.conn)