diff --git a/doc/source/whatsnew/v1.2.2.rst b/doc/source/whatsnew/v1.2.2.rst
index 63e793c013497..8e69bf5e1991a 100644
--- a/doc/source/whatsnew/v1.2.2.rst
+++ b/doc/source/whatsnew/v1.2.2.rst
@@ -21,6 +21,7 @@ Fixed regressions
 - Fixed regression in :meth:`~DataFrame.to_pickle` failing to create bz2/xz compressed pickle files with ``protocol=5`` (:issue:`39002`)
 - Fixed regression in :func:`pandas.testing.assert_series_equal` and :func:`pandas.testing.assert_frame_equal` always raising ``AssertionError`` when comparing extension dtypes (:issue:`39410`)
 - Fixed regression in :meth:`~DataFrame.to_csv` opening ``codecs.StreamWriter`` in binary mode instead of in text mode and ignoring user-provided ``mode`` (:issue:`39247`)
+- Fixed regression in :meth:`~DataFrame.to_excel` creating corrupt files when appending (``mode="a"``) to an existing file (:issue:`39576`)
 - Fixed regression in :meth:`DataFrame.transform` failing in case of an empty DataFrame or Series (:issue:`39636`)
 - Fixed regression in :meth:`core.window.rolling.Rolling.count` where the ``min_periods`` argument would be set to ``0`` after the operation (:issue:`39554`)
 -
diff --git a/pandas/io/excel/_openpyxl.py b/pandas/io/excel/_openpyxl.py
index 64c64b5009b0c..b53db6c726c4d 100644
--- a/pandas/io/excel/_openpyxl.py
+++ b/pandas/io/excel/_openpyxl.py
@@ -1,6 +1,7 @@
 from __future__ import annotations
 
 from distutils.version import LooseVersion
+import mmap
 from typing import TYPE_CHECKING, Dict, List, Optional
 
 import numpy as np
@@ -40,6 +41,7 @@ def __init__(
             from openpyxl import load_workbook
 
             self.book = load_workbook(self.handles.handle)
+            self.handles.handle.seek(0)
         else:
             # Create workbook object with default optimized_write=True.
             self.book = Workbook()
@@ -52,6 +54,9 @@ def save(self):
         Save workbook to disk.
         """
         self.book.save(self.handles.handle)
+        if "r+" in self.mode and not isinstance(self.handles.handle, mmap.mmap):
+            # truncate file to the written content
+            self.handles.handle.truncate()
 
     @classmethod
     def _convert_to_style_kwargs(cls, style_dict: dict) -> Dict[str, Serialisable]:
diff --git a/pandas/tests/io/excel/test_openpyxl.py b/pandas/tests/io/excel/test_openpyxl.py
index 640501baffc62..b365f4edab83c 100644
--- a/pandas/tests/io/excel/test_openpyxl.py
+++ b/pandas/tests/io/excel/test_openpyxl.py
@@ -1,4 +1,5 @@
 from distutils.version import LooseVersion
+from pathlib import Path
 
 import numpy as np
 import pytest
@@ -149,3 +150,22 @@ def test_read_with_bad_dimension(datapath, ext, header, expected_data, filename)
     result = pd.read_excel(path, header=header)
     expected = DataFrame(expected_data)
     tm.assert_frame_equal(result, expected)
+
+
+def test_append_mode_file(ext):
+    # GH 39576
+    df = DataFrame()
+
+    with tm.ensure_clean(ext) as f:
+        df.to_excel(f, engine="openpyxl")
+
+        with ExcelWriter(f, mode="a", engine="openpyxl") as writer:
+            df.to_excel(writer)
+
+        # make sure that zip files are not concatenated by making sure that
+        # "docProps/app.xml" only occurs twice in the file
+        data = Path(f).read_bytes()
+        first = data.find(b"docProps/app.xml")
+        second = data.find(b"docProps/app.xml", first + 1)
+        third = data.find(b"docProps/app.xml", second + 1)
+        assert second != -1 and third == -1