diff --git a/doc/source/whatsnew/v2.0.0.rst b/doc/source/whatsnew/v2.0.0.rst
index 5c635f2d9d3be..d6479a555a1b4 100644
--- a/doc/source/whatsnew/v2.0.0.rst
+++ b/doc/source/whatsnew/v2.0.0.rst
@@ -782,6 +782,7 @@ Datetimelike
 - Bug in ``pandas.tseries.holiday.Holiday`` where a half-open date interval causes inconsistent return types from :meth:`USFederalHolidayCalendar.holidays` (:issue:`49075`)
 - Bug in rendering :class:`DatetimeIndex` and :class:`Series` and :class:`DataFrame` with timezone-aware dtypes with ``dateutil`` or ``zoneinfo`` timezones near daylight-savings transitions (:issue:`49684`)
 - Bug in :func:`to_datetime` was raising ``ValueError`` when parsing :class:`Timestamp`, ``datetime.datetime``, ``datetime.date``, or ``np.datetime64`` objects when non-ISO8601 ``format`` was passed (:issue:`49298`, :issue:`50036`)
+- Bug in :func:`to_datetime` was raising ``ValueError`` when parsing empty string and non-ISO8601 format was passed. Now, empty strings will be parsed as :class:`NaT`, for compatibility with how is done for ISO8601 formats (:issue:`50251`)
 - Bug in :class:`Timestamp` was showing ``UserWarning``, which was not actionable by users, when parsing non-ISO8601 delimited date strings (:issue:`50232`)
 -
 
diff --git a/pandas/_libs/tslibs/strptime.pyx b/pandas/_libs/tslibs/strptime.pyx
index 760364d1b86b4..55de1fc624adf 100644
--- a/pandas/_libs/tslibs/strptime.pyx
+++ b/pandas/_libs/tslibs/strptime.pyx
@@ -157,7 +157,7 @@ def array_strptime(
     for i in range(n):
         val = values[i]
         if isinstance(val, str):
-            if val in nat_strings:
+            if len(val) == 0 or val in nat_strings:
                 iresult[i] = NPY_NAT
                 continue
         elif checknull_with_nat_and_na(val):
diff --git a/pandas/tests/tools/test_to_datetime.py b/pandas/tests/tools/test_to_datetime.py
index c4c60b6c4231e..7e1a3e9129a12 100644
--- a/pandas/tests/tools/test_to_datetime.py
+++ b/pandas/tests/tools/test_to_datetime.py
@@ -2030,17 +2030,13 @@ def test_to_datetime_timezone_name(self):
         assert result == expected
 
     @td.skip_if_not_us_locale
-    def test_to_datetime_with_apply_with_empty_str(self, cache):
+    @pytest.mark.parametrize("errors", ["raise", "coerce", "ignore"])
+    def test_to_datetime_with_apply_with_empty_str(self, cache, errors):
         # this is only locale tested with US/None locales
-        # GH 5195
+        # GH 5195, GH50251
         # with a format and coerce a single item to_datetime fails
         td = Series(["May 04", "Jun 02", ""], index=[1, 2, 3])
-        msg = r"time data '' does not match format '%b %y' \(match\)"
-        with pytest.raises(ValueError, match=msg):
-            to_datetime(td, format="%b %y", errors="raise", cache=cache)
-        with pytest.raises(ValueError, match=msg):
-            td.apply(to_datetime, format="%b %y", errors="raise", cache=cache)
-        expected = to_datetime(td, format="%b %y", errors="coerce", cache=cache)
+        expected = to_datetime(td, format="%b %y", errors=errors, cache=cache)
 
         result = td.apply(
             lambda x: to_datetime(x, format="%b %y", errors="coerce", cache=cache)
@@ -2987,24 +2983,24 @@ def test_na_to_datetime(nulls_fixture, klass):
         assert result[0] is NaT
 
 
-def test_empty_string_datetime_coerce_format():
-    # GH13044
-    td = Series(["03/24/2016", "03/25/2016", ""])
-    format = "%m/%d/%Y"
+@pytest.mark.parametrize("errors", ["raise", "coerce", "ignore"])
+@pytest.mark.parametrize(
+    "args, format",
+    [
+        (["03/24/2016", "03/25/2016", ""], "%m/%d/%Y"),
+        (["2016-03-24", "2016-03-25", ""], "%Y-%m-%d"),
+    ],
+    ids=["non-ISO8601", "ISO8601"],
+)
+def test_empty_string_datetime(errors, args, format):
+    # GH13044, GH50251
+    td = Series(args)
 
     # coerce empty string to pd.NaT
-    result = to_datetime(td, format=format, errors="coerce")
+    result = to_datetime(td, format=format, errors=errors)
     expected = Series(["2016-03-24", "2016-03-25", NaT], dtype="datetime64[ns]")
     tm.assert_series_equal(expected, result)
 
-    # raise an exception in case a format is given
-    with pytest.raises(ValueError, match="does not match format"):
-        to_datetime(td, format=format, errors="raise")
-
-    # still raise an exception in case no format is given
-    with pytest.raises(ValueError, match="does not match format"):
-        to_datetime(td, errors="raise")
-
 
 def test_empty_string_datetime_coerce__unit():
     # GH13044