diff --git a/.kokoro/build.sh b/.kokoro/build.sh
index c8cb87e..32cfc83 100755
--- a/.kokoro/build.sh
+++ b/.kokoro/build.sh
@@ -41,7 +41,7 @@ python3 -m pip install --upgrade --quiet nox
 python3 -m nox --version
 
 # If this is a continuous build, send the test log to the FlakyBot.
-# See https://github.com/googleapis/repo-automation-bots/tree/master/packages/flakybot.
+# See https://github.com/googleapis/repo-automation-bots/tree/main/packages/flakybot.
 if [[ $KOKORO_BUILD_ARTIFACTS_SUBDIR = *"continuous"* ]]; then
   cleanup() {
     chmod +x $KOKORO_GFILE_DIR/linux_amd64/flakybot
diff --git a/.kokoro/test-samples-impl.sh b/.kokoro/test-samples-impl.sh
index 311a8d5..8a324c9 100755
--- a/.kokoro/test-samples-impl.sh
+++ b/.kokoro/test-samples-impl.sh
@@ -80,7 +80,7 @@ for file in samples/**/requirements.txt; do
     EXIT=$?
 
     # If this is a periodic build, send the test log to the FlakyBot.
-    # See https://github.com/googleapis/repo-automation-bots/tree/master/packages/flakybot.
+    # See https://github.com/googleapis/repo-automation-bots/tree/main/packages/flakybot.
     if [[ $KOKORO_BUILD_ARTIFACTS_SUBDIR = *"periodic"* ]]; then
       chmod +x $KOKORO_GFILE_DIR/linux_amd64/flakybot
       $KOKORO_GFILE_DIR/linux_amd64/flakybot
diff --git a/CONTRIBUTING.rst b/CONTRIBUTING.rst
index 02716b0..e338376 100644
--- a/CONTRIBUTING.rst
+++ b/CONTRIBUTING.rst
@@ -50,9 +50,9 @@ You'll have to create a development environment using a Git checkout:
    # Configure remotes such that you can pull changes from the googleapis/python-life-sciences
    # repository into your local repository.
    $ git remote add upstream git@github.com:googleapis/python-life-sciences.git
-   # fetch and merge changes from upstream into master
+   # fetch and merge changes from upstream into main
    $ git fetch upstream
-   $ git merge upstream/master
+   $ git merge upstream/main
 
 Now your local repo is set up such that you will push changes to your GitHub
 repo, from which you can submit a pull request.
@@ -110,12 +110,12 @@ Coding Style
   variables::
 
    export GOOGLE_CLOUD_TESTING_REMOTE="upstream"
-   export GOOGLE_CLOUD_TESTING_BRANCH="master"
+   export GOOGLE_CLOUD_TESTING_BRANCH="main"
 
   By doing this, you are specifying the location of the most up-to-date
   version of ``python-life-sciences``. The the suggested remote name ``upstream``
   should point to the official ``googleapis`` checkout and the
-  the branch should be the main branch on that remote (``master``).
+  the branch should be the main branch on that remote (``main``).
 
 - This repository contains configuration for the
   `pre-commit <https://pre-commit.com/>`__ tool, which automates checking
@@ -209,7 +209,7 @@ The `description on PyPI`_ for the project comes directly from the
 ``README``. Due to the reStructuredText (``rst``) parser used by
 PyPI, relative links which will work on GitHub (e.g. ``CONTRIBUTING.rst``
 instead of
-``https://github.com/googleapis/python-life-sciences/blob/master/CONTRIBUTING.rst``)
+``https://github.com/googleapis/python-life-sciences/blob/main/CONTRIBUTING.rst``)
 may cause problems creating links or rendering the description.
 
 .. _description on PyPI: https://pypi.org/project/google-cloud-life-sciences
@@ -234,7 +234,7 @@ We support:
 
 Supported versions can be found in our ``noxfile.py`` `config`_.
 
-.. _config: https://github.com/googleapis/python-life-sciences/blob/master/noxfile.py
+.. _config: https://github.com/googleapis/python-life-sciences/blob/main/noxfile.py
 
 
 We also explicitly decided to support Python 3 beginning with version 3.6.
diff --git a/owlbot.py b/owlbot.py
index bf2fa52..d943546 100644
--- a/owlbot.py
+++ b/owlbot.py
@@ -39,3 +39,32 @@
 # ----------------------------------------------------------------------------
 
 s.shell.run(["nox", "-s", "blacken"], hide_output=False)
+
+# ----------------------------------------------------------------------------
+# Main Branch migration
+# ----------------------------------------------------------------------------
+
+s.replace(
+  "*.rst",
+  "master",
+  "main"
+)
+
+s.replace(
+  "*.rst",
+  "google-cloud-python/blob/main",
+  "google-cloud-python/blob/master"
+)
+
+s.replace(
+  "CONTRIBUTING.rst",
+  "kubernetes/community/blob/main",
+  "kubernetes/community/blob/master"
+)
+
+s.replace(
+  ".kokoro/*",
+  "master",
+  "main"
+)
+