diff --git a/crates/uv/src/commands/tool/run.rs b/crates/uv/src/commands/tool/run.rs
index e1af04dd3..e13160261 100644
--- a/crates/uv/src/commands/tool/run.rs
+++ b/crates/uv/src/commands/tool/run.rs
@@ -1,5 +1,6 @@
 use std::fmt::Display;
 use std::fmt::Write;
+use std::path::Path;
 use std::path::PathBuf;
 use std::str::FromStr;
 
@@ -18,6 +19,7 @@ use uv_configuration::{Concurrency, PreviewMode};
 use uv_distribution_types::{
     Name, NameRequirementSpecification, UnresolvedRequirement, UnresolvedRequirementSpecification,
 };
+use uv_fs::Simplified;
 use uv_installer::{SatisfiesResult, SitePackages};
 use uv_normalize::PackageName;
 use uv_pep440::{VersionSpecifier, VersionSpecifiers};
@@ -92,6 +94,12 @@ pub(crate) async fn run(
     printer: Printer,
     preview: PreviewMode,
 ) -> anyhow::Result<ExitStatus> {
+    /// Whether or not a path looks like a Python script based on the file extension.
+    fn has_python_script_ext(path: &Path) -> bool {
+        path.extension()
+            .is_some_and(|ext| ext.eq_ignore_ascii_case("py") || ext.eq_ignore_ascii_case("pyw"))
+    }
+
     let Some(command) = command else {
         // When a command isn't provided, we'll show a brief help including available tools
         show_help(invocation_source, &cache, printer).await?;
@@ -105,9 +113,46 @@ pub(crate) async fn run(
     };
 
     let Some(target) = target.to_str() else {
-        return Err(anyhow::anyhow!("Tool command could not be parsed as UTF-8 string. Use `--from` to specify the package name."));
+        return Err(anyhow::anyhow!("Tool command could not be parsed as UTF-8 string. Use `--from` to specify the package name"));
     };
 
+    if let Some(ref from) = from {
+        if has_python_script_ext(Path::new(from)) {
+            let package_name = PackageName::from_str(from)?;
+            return Err(anyhow::anyhow!(
+                "It looks you provided a Python script to `--from`, which is not supported\n\n{}{} If you meant to run a command from the `{}` package, use the normalized package name instead to disambiguate, e.g., `{}`",
+                "hint".bold().cyan(),
+                ":".bold(),
+                package_name.cyan(),
+                format!("{} --from {} {}", invocation_source, package_name.cyan(), target),
+            ));
+        }
+    } else {
+        let target_path = Path::new(target);
+        if has_python_script_ext(target_path) {
+            return if target_path.try_exists()? {
+                Err(anyhow::anyhow!(
+                    "It looks you tried to run a Python script at `{}`, which is not supported by `{}`\n\n{}{} Use `{}` instead",
+                    target_path.user_display(),
+                    invocation_source,
+                    "hint".bold().cyan(),
+                    ":".bold(),
+                    format!("uv run {}", target_path.user_display().cyan()),
+                ))
+            } else {
+                let package_name = PackageName::from_str(target)?;
+                Err(anyhow::anyhow!(
+                    "It looks you provided a Python script to run, which is not supported supported by `{}`\n\n{}{} We did not find a script at the requested path. If you meant to run a command from the `{}` package, pass the normalized package name to `--from` to disambiguate, e.g., `{}`",
+                    invocation_source,
+                    "hint".bold().cyan(),
+                    ":".bold(),
+                    package_name.cyan(),
+                    format!("{} --from {} {}", invocation_source, package_name, target),
+                ))
+            };
+        }
+    }
+
     let request = ToolRequest::parse(target, from.as_deref());
 
     // If the user passed, e.g., `ruff@latest`, refresh the cache.
diff --git a/crates/uv/tests/it/tool_run.rs b/crates/uv/tests/it/tool_run.rs
index 919393c39..d0beb79c8 100644
--- a/crates/uv/tests/it/tool_run.rs
+++ b/crates/uv/tests/it/tool_run.rs
@@ -1760,7 +1760,7 @@ fn tool_run_python_at_version() {
     success: false
     exit_code: 2
     ----- stdout -----
-    
+
     ----- stderr -----
     error: Invalid version request: 3.300
     "###);
@@ -1962,3 +1962,117 @@ fn tool_run_verbatim_name() {
     Resolved [N] packages in [TIME]
     ");
 }
+
+#[test]
+fn tool_run_with_existing_py_script() -> anyhow::Result<()> {
+    let context = TestContext::new("3.12").with_filtered_counts();
+    context.temp_dir.child("script.py").touch()?;
+
+    uv_snapshot!(context.filters(), context.tool_run().arg("script.py"), @r"
+    success: false
+    exit_code: 2
+    ----- stdout -----
+
+    ----- stderr -----
+    error: It looks you tried to run a Python script at `script.py`, which is not supported by `uv tool run`
+
+    hint: Use `uv run script.py` instead
+    ");
+    Ok(())
+}
+
+#[test]
+fn tool_run_with_existing_pyw_script() -> anyhow::Result<()> {
+    let context = TestContext::new("3.12").with_filtered_counts();
+    context.temp_dir.child("script.pyw").touch()?;
+
+    // We treat arguments before the command as uv arguments
+    uv_snapshot!(context.filters(), context.tool_run()
+        .arg("script.pyw"), @r"
+    success: false
+    exit_code: 2
+    ----- stdout -----
+
+    ----- stderr -----
+    error: It looks you tried to run a Python script at `script.pyw`, which is not supported by `uv tool run`
+
+    hint: Use `uv run script.pyw` instead
+    ");
+    Ok(())
+}
+
+#[test]
+fn tool_run_with_nonexistent_py_script() {
+    let context = TestContext::new("3.12").with_filtered_counts();
+
+    // We treat arguments before the command as uv arguments
+    uv_snapshot!(context.filters(), context.tool_run()
+        .arg("script.py"), @r"
+    success: false
+    exit_code: 2
+    ----- stdout -----
+
+    ----- stderr -----
+    error: It looks you provided a Python script to run, which is not supported supported by `uv tool run`
+
+    hint: We did not find a script at the requested path. If you meant to run a command from the `script-py` package, pass the normalized package name to `--from` to disambiguate, e.g., `uv tool run --from script-py script.py`
+    ");
+}
+
+#[test]
+fn tool_run_with_nonexistent_pyw_script() {
+    let context = TestContext::new("3.12").with_filtered_counts();
+
+    // We treat arguments before the command as uv arguments
+    uv_snapshot!(context.filters(), context.tool_run()
+        .arg("script.pyw"), @r"
+    success: false
+    exit_code: 2
+    ----- stdout -----
+
+    ----- stderr -----
+    error: It looks you provided a Python script to run, which is not supported supported by `uv tool run`
+
+    hint: We did not find a script at the requested path. If you meant to run a command from the `script-pyw` package, pass the normalized package name to `--from` to disambiguate, e.g., `uv tool run --from script-pyw script.pyw`
+    ");
+}
+
+#[test]
+fn tool_run_with_from_script() {
+    let context = TestContext::new("3.12").with_filtered_counts();
+
+    // We treat arguments before the command as uv arguments
+    uv_snapshot!(context.filters(), context.tool_run()
+        .arg("--from")
+        .arg("script.py")
+        .arg("ruff"), @r"
+    success: false
+    exit_code: 2
+    ----- stdout -----
+
+    ----- stderr -----
+    error: It looks you provided a Python script to `--from`, which is not supported
+
+    hint: If you meant to run a command from the `script-py` package, use the normalized package name instead to disambiguate, e.g., `uv tool run --from script-py ruff`
+    ");
+}
+
+#[test]
+fn tool_run_with_script_and_from_script() {
+    let context = TestContext::new("3.12").with_filtered_counts();
+
+    // We treat arguments before the command as uv arguments
+    uv_snapshot!(context.filters(), context.tool_run()
+        .arg("--from")
+        .arg("script.py")
+        .arg("other-script.py"), @r"
+    success: false
+    exit_code: 2
+    ----- stdout -----
+
+    ----- stderr -----
+    error: It looks you provided a Python script to `--from`, which is not supported
+
+    hint: If you meant to run a command from the `script-py` package, use the normalized package name instead to disambiguate, e.g., `uv tool run --from script-py other-script.py`
+    ");
+}