diff --git a/modules/cli/src/main/scala/scala/cli/commands/package0/Package.scala b/modules/cli/src/main/scala/scala/cli/commands/package0/Package.scala
index f859c5f581..b1a17a6e95 100644
--- a/modules/cli/src/main/scala/scala/cli/commands/package0/Package.scala
+++ b/modules/cli/src/main/scala/scala/cli/commands/package0/Package.scala
@@ -1,6 +1,4 @@
 package scala.cli.commands.package0
-
-import ai.kien.python.Python
 import caseapp.*
 import caseapp.core.help.HelpFormat
 import coursier.core
@@ -34,7 +32,7 @@ import scala.cli.CurrentParams
 import scala.cli.commands.OptionsHelper.*
 import scala.cli.commands.doc.Doc
 import scala.cli.commands.packaging.Spark
-import scala.cli.commands.run.Run.orPythonDetectionError
+import scala.cli.commands.run.Run.{createPythonInstance, orPythonDetectionError}
 import scala.cli.commands.shared.{HelpCommandGroup, HelpGroup, MainClassOptions, SharedOptions}
 import scala.cli.commands.util.BuildCommandHelpers
 import scala.cli.commands.util.BuildCommandHelpers.*
@@ -1089,7 +1087,7 @@ object Package extends ScalaCommand[PackageOptions] with BuildCommandHelpers {
     val pythonLdFlags =
       if setupPython then
         value {
-          val python       = Python()
+          val python       = value(createPythonInstance().orPythonDetectionError)
           val flagsOrError = python.ldflags
           logger.debug(s"Python ldflags: $flagsOrError")
           flagsOrError.orPythonDetectionError
diff --git a/modules/cli/src/main/scala/scala/cli/commands/repl/Repl.scala b/modules/cli/src/main/scala/scala/cli/commands/repl/Repl.scala
index 676f852566..de45c9c607 100644
--- a/modules/cli/src/main/scala/scala/cli/commands/repl/Repl.scala
+++ b/modules/cli/src/main/scala/scala/cli/commands/repl/Repl.scala
@@ -1,6 +1,4 @@
 package scala.cli.commands.repl
-
-import ai.kien.python.Python
 import caseapp.*
 import caseapp.core.help.HelpFormat
 import coursier.cache.FileCache
@@ -23,7 +21,7 @@ import scala.build.internal.{Constants, Runner}
 import scala.build.options.ScalacOpt.noDashPrefixes
 import scala.build.options.{BuildOptions, JavaOpt, MaybeScalaVersion, ScalaVersionUtil, Scope}
 import scala.cli.CurrentParams
-import scala.cli.commands.run.Run.{orPythonDetectionError, pythonPathEnv}
+import scala.cli.commands.run.Run.{createPythonInstance, orPythonDetectionError, pythonPathEnv}
 import scala.cli.commands.run.RunMode
 import scala.cli.commands.shared.{HelpCommandGroup, HelpGroup, ScalacOptions, SharedOptions}
 import scala.cli.commands.util.BuildCommandHelpers
@@ -311,7 +309,7 @@ object Repl extends ScalaCommand[ReplOptions] with BuildCommandHelpers {
     val (scalapyJavaOpts, scalapyExtraEnv) =
       if (setupPython) {
         val props = value {
-          val python       = Python()
+          val python       = value(createPythonInstance().orPythonDetectionError)
           val propsOrError = python.scalapyProperties
           logger.debug(s"Python Java properties: $propsOrError")
           propsOrError.orPythonDetectionError
diff --git a/modules/cli/src/main/scala/scala/cli/commands/run/Run.scala b/modules/cli/src/main/scala/scala/cli/commands/run/Run.scala
index bf9077d60e..b74604aaf4 100644
--- a/modules/cli/src/main/scala/scala/cli/commands/run/Run.scala
+++ b/modules/cli/src/main/scala/scala/cli/commands/run/Run.scala
@@ -504,7 +504,7 @@ object Run extends ScalaCommand[RunOptions] with BuildCommandHelpers {
         val (pythonExecutable, pythonLibraryPaths, pythonExtraEnv) =
           if (setupPython) {
             val (exec, libPaths) = value {
-              val python                  = Python()
+              val python                  = value(createPythonInstance().orPythonDetectionError)
               val pythonPropertiesOrError = for {
                 paths      <- python.nativeLibraryPaths
                 executable <- python.executable
@@ -586,7 +586,7 @@ object Run extends ScalaCommand[RunOptions] with BuildCommandHelpers {
             val (pythonJavaProps, pythonExtraEnv) =
               if (setupPython) {
                 val scalapyProps = value {
-                  val python       = Python()
+                  val python       = value(createPythonInstance().orPythonDetectionError)
                   val propsOrError = python.scalapyProperties
                   logger.debug(s"Python Java properties: $propsOrError")
                   propsOrError.orPythonDetectionError
@@ -712,8 +712,64 @@ object Run extends ScalaCommand[RunOptions] with BuildCommandHelpers {
       logger = logger
     ).map(f)
 
+  def findHomebrewPython(): Option[os.Path] =
+    if (Properties.isMac) {
+      // Try common Homebrew locations
+      val homebrewPaths = Seq(
+        "/opt/homebrew/bin/python3",
+        "/usr/local/bin/python3"
+      )
+      homebrewPaths
+        .map(os.Path(_, os.pwd))
+        .find { path =>
+          os.exists(path) && {
+            // Verify it has the -config script
+            val configPath = path / os.up / s"${path.last}-config"
+            os.exists(configPath)
+          }
+        }
+    }
+    else None
+
+  def createPythonInstance(): Try[Python] =
+    // Try default Python detection first
+    // If it fails on macOS and Homebrew Python is available, the error message will guide the user
+    Try(Python())
+
   final class PythonDetectionError(cause: Throwable) extends BuildException(
-        s"Error detecting Python environment: ${cause.getMessage}",
+        {
+          val baseMessage = cause.getMessage
+          if (
+            Properties.isMac && baseMessage != null && baseMessage.contains(
+              "-config"
+            ) && baseMessage.contains("does not exist")
+          ) {
+            val homebrewPython = findHomebrewPython()
+            val homebrewHint   = homebrewPython match {
+              case Some(path) =>
+                s"""
+                   |Homebrew Python was found at $path, but it's not being used.
+                   |Ensure Homebrew's bin directory is first in your PATH:
+                   |  export PATH="${path / os.up}:$$PATH"
+                   |""".stripMargin
+              case None =>
+                """
+                  |Consider installing Python via Homebrew:
+                  |  brew install python
+                  |
+                  |Or install Python from https://www.python.org/downloads/
+                  |""".stripMargin
+            }
+            s"""Error detecting Python environment: $baseMessage
+               |
+               |The system Python from CommandLineTools may not include the required -config scripts.
+               |$homebrewHint
+               |
+               |Alternatively, you can disable Python setup with --python=false""".stripMargin
+          }
+          else
+            s"Error detecting Python environment: $baseMessage"
+        },
         cause = cause
       )