diff --git a/crates/uv-cli/src/lib.rs b/crates/uv-cli/src/lib.rs
index 1d5e4739a..1887ba9be 100644
--- a/crates/uv-cli/src/lib.rs
+++ b/crates/uv-cli/src/lib.rs
@@ -2932,6 +2932,15 @@ pub struct RunArgs {
     /// By default, environment modifications are omitted, but enabled under `--verbose`.
     #[arg(long, env = EnvVars::UV_SHOW_RESOLUTION, value_parser = clap::builder::BoolishValueParser::new(), hide = true)]
     pub show_resolution: bool,
+
+    /// Number of times that `uv run` will allow recursive invocations.
+    ///
+    /// The current recursion depth is tracked by environment variable. If environment variables are
+    /// cleared, uv will fail to detect the recursion depth.
+    ///
+    /// If uv reaches the maximum recursion depth, it will exit with an error.
+    #[arg(long, hide = true, env = EnvVars::UV_RUN_MAX_RECURSION_DEPTH)]
+    pub max_recursion_depth: Option<u32>,
 }
 
 #[derive(Args)]
diff --git a/crates/uv-static/src/env_vars.rs b/crates/uv-static/src/env_vars.rs
index 36085c828..8927509cd 100644
--- a/crates/uv-static/src/env_vars.rs
+++ b/crates/uv-static/src/env_vars.rs
@@ -623,4 +623,14 @@ impl EnvVars {
 
     /// Enables fetching files stored in Git LFS when installing a package from a Git repository.
     pub const UV_GIT_LFS: &'static str = "UV_GIT_LFS";
+
+    /// Number of times that `uv run` has been recursively invoked. Used to guard against infinite
+    /// recursion, e.g., when `uv run`` is used in a script shebang.
+    #[attr_hidden]
+    pub const UV_RUN_RECURSION_DEPTH: &'static str = "UV_RUN_RECURSION_DEPTH";
+
+    /// Number of times that `uv run` will allow recursive invocations, before exiting with an
+    /// error.
+    #[attr_hidden]
+    pub const UV_RUN_MAX_RECURSION_DEPTH: &'static str = "UV_RUN_MAX_RECURSION_DEPTH";
 }
diff --git a/crates/uv/src/commands/project/run.rs b/crates/uv/src/commands/project/run.rs
index 8ed679e48..3d034fc3e 100644
--- a/crates/uv/src/commands/project/run.rs
+++ b/crates/uv/src/commands/project/run.rs
@@ -1,4 +1,5 @@
 use std::borrow::Cow;
+use std::env::VarError;
 use std::ffi::OsString;
 use std::fmt::Write;
 use std::io::Read;
@@ -91,7 +92,23 @@ pub(crate) async fn run(
     env_file: Vec<PathBuf>,
     no_env_file: bool,
     preview: PreviewMode,
+    max_recursion_depth: u32,
 ) -> anyhow::Result<ExitStatus> {
+    // Check if max recursion depth was exceeded. This most commonly happens
+    // for scripts with a shebang line like `#!/usr/bin/env -S uv run`, so try
+    // to provide guidance for that case.
+    let recursion_depth = read_recursion_depth_from_environment_variable()?;
+    if recursion_depth > max_recursion_depth {
+        bail!(
+            r"
+`uv run` was recursively invoked {recursion_depth} times which exceeds the limit of {max_recursion_depth}.
+
+hint: If you are running a script with `{}` in the shebang, you may need to include the `{}` flag.",
+            "uv run".green(),
+            "--script".green(),
+        );
+    }
+
     // These cases seem quite complex because (in theory) they should change the "current package".
     // Let's ban them entirely for now.
     let mut requirements_from_stdin: bool = false;
@@ -1034,6 +1051,12 @@ pub(crate) async fn run(
     )?;
     process.env(EnvVars::PATH, new_path);
 
+    // Increment recursion depth counter.
+    process.env(
+        EnvVars::UV_RUN_RECURSION_DEPTH,
+        (recursion_depth + 1).to_string(),
+    );
+
     // Ensure `VIRTUAL_ENV` is set.
     if interpreter.is_virtualenv() {
         process.env(EnvVars::VIRTUAL_ENV, interpreter.sys_prefix().as_os_str());
@@ -1464,3 +1487,24 @@ fn is_python_zipapp(target: &Path) -> bool {
     }
     false
 }
+
+/// Read and parse recursion depth from the environment.
+///
+/// Returns Ok(0) if `EnvVars::UV_RUN_RECURSION_DEPTH` is not set.
+///
+/// Returns an error if `EnvVars::UV_RUN_RECURSION_DEPTH` is set to a value
+/// that cannot ber parsed as an integer.
+fn read_recursion_depth_from_environment_variable() -> anyhow::Result<u32> {
+    let envvar = match std::env::var(EnvVars::UV_RUN_RECURSION_DEPTH) {
+        Ok(val) => val,
+        Err(VarError::NotPresent) => return Ok(0),
+        Err(e) => {
+            return Err(e)
+                .with_context(|| format!("invalid value for {}", EnvVars::UV_RUN_RECURSION_DEPTH))
+        }
+    };
+
+    envvar
+        .parse::<u32>()
+        .with_context(|| format!("invalid value for {}", EnvVars::UV_RUN_RECURSION_DEPTH))
+}
diff --git a/crates/uv/src/lib.rs b/crates/uv/src/lib.rs
index b3f735fcd..befe8d812 100644
--- a/crates/uv/src/lib.rs
+++ b/crates/uv/src/lib.rs
@@ -1516,6 +1516,7 @@ async fn run_project(
                 args.env_file,
                 args.no_env_file,
                 globals.preview,
+                args.max_recursion_depth,
             ))
             .await
         }
diff --git a/crates/uv/src/settings.rs b/crates/uv/src/settings.rs
index 91ba1eba2..f5864066b 100644
--- a/crates/uv/src/settings.rs
+++ b/crates/uv/src/settings.rs
@@ -299,9 +299,16 @@ pub(crate) struct RunSettings {
     pub(crate) settings: ResolverInstallerSettings,
     pub(crate) env_file: Vec<PathBuf>,
     pub(crate) no_env_file: bool,
+    pub(crate) max_recursion_depth: u32,
 }
 
 impl RunSettings {
+    // Default value for UV_RUN_MAX_RECURSION_DEPTH if unset. This is large
+    // enough that it's unlikely a user actually needs this recursion depth,
+    // but short enough that we detect recursion quickly enough to avoid OOMing
+    // or hanging for a long time.
+    const DEFAULT_MAX_RECURSION_DEPTH: u32 = 100;
+
     /// Resolve the [`RunSettings`] from the CLI and filesystem configuration.
     #[allow(clippy::needless_pass_by_value)]
     pub(crate) fn resolve(args: RunArgs, filesystem: Option<FilesystemOptions>) -> Self {
@@ -344,6 +351,7 @@ impl RunSettings {
             show_resolution,
             env_file,
             no_env_file,
+            max_recursion_depth,
         } = args;
 
         let install_mirrors = filesystem
@@ -403,6 +411,7 @@ impl RunSettings {
             env_file,
             no_env_file,
             install_mirrors,
+            max_recursion_depth: max_recursion_depth.unwrap_or(Self::DEFAULT_MAX_RECURSION_DEPTH),
         }
     }
 }
diff --git a/crates/uv/tests/it/run.rs b/crates/uv/tests/it/run.rs
index f20ec3c9a..05b691556 100644
--- a/crates/uv/tests/it/run.rs
+++ b/crates/uv/tests/it/run.rs
@@ -4202,3 +4202,41 @@ fn run_without_overlay() -> Result<()> {
 
     Ok(())
 }
+
+/// See: <https://github.com/astral-sh/uv/issues/11220>
+#[cfg(unix)]
+#[test]
+fn detect_infinite_recursion() -> Result<()> {
+    use crate::common::get_bin;
+    use indoc::formatdoc;
+    use std::os::unix::fs::PermissionsExt;
+
+    let context = TestContext::new("3.12");
+
+    let test_script = context.temp_dir.child("main");
+    test_script.write_str(&formatdoc! { r#"
+        #!{uv} run
+
+        print("Hello, world!")
+    "#, uv = get_bin().display()})?;
+
+    fs_err::set_permissions(test_script.path(), PermissionsExt::from_mode(0o0744))?;
+
+    let mut cmd = std::process::Command::new(test_script.as_os_str());
+
+    // Set the max recursion depth to a lower amount to speed up testing.
+    cmd.env("UV_RUN_MAX_RECURSION_DEPTH", "5");
+
+    uv_snapshot!(context.filters(), cmd, @r###"
+    success: false
+    exit_code: 2
+    ----- stdout -----
+
+    ----- stderr -----
+    error: `uv run` was recursively invoked 6 times which exceeds the limit of 5.
+
+    hint: If you are running a script with `uv run` in the shebang, you may need to include the `--script` flag.
+    "###);
+
+    Ok(())
+}