diff --git a/python/lib/dependabot/python/update_checker/pipenv_version_resolver.rb b/python/lib/dependabot/python/update_checker/pipenv_version_resolver.rb
index c6d8f8c2d9f9..f969903c2fa5 100644
--- a/python/lib/dependabot/python/update_checker/pipenv_version_resolver.rb
+++ b/python/lib/dependabot/python/update_checker/pipenv_version_resolver.rb
@@ -39,6 +39,12 @@ class PipenvVersionResolver
         UNSUPPORTED_DEP_REGEX =
           /"python setup\.py egg_info".*(?:#{UNSUPPORTED_DEPS.join("|")})/.
           freeze
+        PIPENV_INSTALLATION_ERROR = "pipenv.patched.notpip._internal."\
+                                    "exceptions.InstallationError: "\
+                                    "Command \"python setup.py egg_info\" "\
+                                    "failed with error code 1 in"
+        PIPENV_INSTALLATION_ERROR_REGEX =
+          %r{#{Regexp.quote(PIPENV_INSTALLATION_ERROR)}.+/(?<name>.+)/$}.freeze
 
         attr_reader :dependency, :dependency_files, :credentials
 
@@ -169,7 +175,6 @@ def handle_pipenv_errors(error)
             return if error.message.match?(/#{Regexp.quote(dependency.name)}/i)
           end
 
-          puts error.message
           if error.message.match?(GIT_DEPENDENCY_UNREACHABLE_REGEX)
             url = error.message.match(GIT_DEPENDENCY_UNREACHABLE_REGEX).
                   named_captures.fetch("url")
@@ -232,6 +237,10 @@ def handle_pipenv_errors_resolving_original_reqs(error)
             raise DependencyFileNotResolvable, msg
           end
 
+          # NOTE: Pipenv masks the actualy error, see this issue for updates:
+          # https://github.com/pypa/pipenv/issues/2791
+          handle_pipenv_installation_error(error.message) if error.message.match?(PIPENV_INSTALLATION_ERROR_REGEX)
+
           # Raise an unhandled error, as this could be a problem with
           # Dependabot's infrastructure, rather than the Pipfile
           raise
@@ -257,6 +266,19 @@ def clean_error_message(message)
           msg.gsub(/http.*?(?=\s)/, "<redacted>")
         end
 
+        def handle_pipenv_installation_error(error_message)
+          # Find the dependency that's causing resolution to fail
+          dependency_name = error_message.match(PIPENV_INSTALLATION_ERROR_REGEX).named_captures["name"]
+          raise unless dependency_name
+
+          msg = "Pipenv failed to install \"#{dependency_name}\". This could be caused by missing system "\
+                "dependencies that can't be installed by Dependabot or required installation flags.\n\n"\
+                "Error output from running \"pipenv lock\":\n"\
+                "#{clean_error_message(error_message)}"
+
+          raise DependencyFileNotResolvable, msg
+        end
+
         def write_temporary_dependency_files(updated_req: nil,
                                              update_pipfile: true)
           dependency_files.each do |file|
diff --git a/python/spec/dependabot/python/update_checker/pipenv_version_resolver_spec.rb b/python/spec/dependabot/python/update_checker/pipenv_version_resolver_spec.rb
index e432cb673b1e..6950d41d9efb 100644
--- a/python/spec/dependabot/python/update_checker/pipenv_version_resolver_spec.rb
+++ b/python/spec/dependabot/python/update_checker/pipenv_version_resolver_spec.rb
@@ -469,6 +469,35 @@
           end
       end
     end
+
+    context "with a missing system libary" do
+      # NOTE: Attempt to update an unrelated dependency (tensorflow) to cause
+      # resolution to fail for rtree which has a system dependency on
+      # libspatialindex which isn't installed in dependabot-core's Dockerfile.
+      let(:dependency_files) do
+        project_dependency_files("pipenv/missing-system-library")
+      end
+      let(:updated_requirement) { "==2.3.1" }
+      let(:dependency_name) { "tensorflow" }
+      let(:dependency_version) { "2.1.0" }
+      let(:dependency_requirements) do
+        [{
+          file: "Pipfile",
+          requirement: "==2.1.0",
+          groups: ["default"],
+          source: nil
+        }]
+      end
+
+      it "raises a helpful error" do
+        expect { subject }.
+          to raise_error(Dependabot::DependencyFileNotResolvable) do |error|
+            expect(error.message).to include(
+              "Pipenv failed to install \"rtree\""
+            )
+          end
+      end
+    end
   end
 
   describe "#resolvable?" do
diff --git a/python/spec/fixtures/projects/pipenv/missing-system-library/Pipfile b/python/spec/fixtures/projects/pipenv/missing-system-library/Pipfile
new file mode 100644
index 000000000000..ed3d0bd217ea
--- /dev/null
+++ b/python/spec/fixtures/projects/pipenv/missing-system-library/Pipfile
@@ -0,0 +1,8 @@
+[[source]]
+url = "https://pypi.org/simple"
+verify_ssl = true
+name = "pypi"
+
+[packages]
+rtree = "==0.9.3"
+tensorflow = "==2.1.0"
diff --git a/python/spec/fixtures/projects/pipenv/missing-system-library/Pipfile.lock b/python/spec/fixtures/projects/pipenv/missing-system-library/Pipfile.lock
new file mode 100644
index 000000000000..b7af358bae96
--- /dev/null
+++ b/python/spec/fixtures/projects/pipenv/missing-system-library/Pipfile.lock
@@ -0,0 +1,41 @@
+{
+    "_meta": {
+        "hash": {
+            "sha256": "e98725a3545acb9f6a84023a297838e6edf163ef50824694b0ebeb0d372ca0f5"
+        },
+        "pipfile-spec": 6,
+        "sources": [
+            {
+                "name": "pypi",
+                "url": "https://pypi.org/simple",
+                "verify_ssl": true
+            }
+        ]
+    },
+    "default": {
+        "rtree": {
+            "hashes": [
+                "sha256:cae327e2c03b3da4ea40d0fdf68f3e55fe9f302c56b9f31e1bfeb36dbea73f44"
+            ],
+            "index": "pypi",
+            "version": "==0.9.3"
+        },
+        "tensorflow": {
+            "hashes": [
+                "sha256:1cf129ccda0aea616b122f34b0c4bc39da959d34c4a4d8c23ed944555c5e47ab",
+                "sha256:2e8fc9764b7ea87687a4c80c2fbde69aeeb459a536eb5a591938d7931ab004c2",
+                "sha256:33e4b16e8f8905ee088bf8f413dcce2820b777fdf7f799009b3a47f354ebb23f",
+                "sha256:513d48dd751e0076d1b1e5e498e3522891305bedd2840f3cb4b1c57ffcb7d97d",
+                "sha256:5cfa729fc71f6f2dca0ea77ebe768ea293e723e22ecb086a0b3ab26cc1776e37",
+                "sha256:7bad8ea686a1f33d9dac13eb578c4597346789d4f826980c8bbcfbd08e7dc921",
+                "sha256:8c0fae0f9f772ed7e3370f1b286f88c27debbcf09468e5036670ea2c67e239ec",
+                "sha256:92c4f1c939de438fbe484d011e5eebe059fc8e5244cfe32a81c6891b3357d109",
+                "sha256:c420e70d4127c2ac00054aece54cf04a1a43d5d4f25de90267f247873f1bd5a8",
+                "sha256:e631f55cf30054fee3230c89a7f998fd08748aa3045651a5a760cec2c5b9f9d6",
+                "sha256:e877fbf373d5be42fb118269df1670b8d3c0df9be223904a2584a8f8ed23b082"
+            ],
+            "index": "pypi",
+            "version": "==2.1.0"
+        }
+    }
+}