diff --git a/crates/uv/src/commands/diagnostics.rs b/crates/uv/src/commands/diagnostics.rs
index 2ee04220a46cf..6e3e101ea21a1 100644
--- a/crates/uv/src/commands/diagnostics.rs
+++ b/crates/uv/src/commands/diagnostics.rs
@@ -1,5 +1,7 @@
 use std::str::FromStr;
 use std::sync::{Arc, LazyLock};
+use std::io::{BufRead, BufReader};
+use std::path::{Path, PathBuf};
 
 use owo_colors::OwoColorize;
 use rustc_hash::FxHashMap;
@@ -477,3 +479,22 @@ fn format_chain(name: &PackageName, version: Option<&Version>, chain: &Derivatio
     }
     message
 }
+
+
+pub(crate) fn extract_python_from_shebang(script_path: &Path) -> Option<PathBuf> {
+    let file = std::fs::File::open(script_path).ok()?;
+    let mut reader = BufReader::new(file);
+    let mut first_line = String::new();
+    reader.read_line(&mut first_line).ok()?;
+
+    // Check if it starts with shebang
+    let shebang = first_line.strip_prefix("#!")?;
+    let shebang = shebang.trim();
+
+    if shebang.contains("python") {
+        let interpreter = shebang.split_whitespace().next()?;
+        Some(PathBuf::from(interpreter))
+    } else {
+        None
+    }
+}
diff --git a/crates/uv/src/commands/project/run.rs b/crates/uv/src/commands/project/run.rs
index dc8b201d0f6e8..f9544ccf49a20 100644
--- a/crates/uv/src/commands/project/run.rs
+++ b/crates/uv/src/commands/project/run.rs
@@ -1319,9 +1319,30 @@ hint: If you are running a script with `{}` in the shebang, you may need to incl
     // Spawn and wait for completion
     // Standard input, output, and error streams are all inherited
     // TODO(zanieb): Throw a nicer error message if the command is not found
-    let handle = process
-        .spawn()
-        .with_context(|| format!("Failed to spawn: `{}`", command.display_executable()))?;
+    let handle = match process.spawn() {
+        Ok(handle) => Ok(handle),
+        Err(err) if err.kind() == std::io::ErrorKind::NotFound => {
+            // Check if the error is due to a missing Python interpreter in the script's shebang.
+            let script_path = interpreter.scripts().join(command.executable());
+            if script_path.exists() {
+                if let Some(python_path) = crate::commands::diagnostics::extract_python_from_shebang(&script_path) {
+                    if !python_path.exists() {
+                        writeln!(
+                            printer.stderr(),
+                            "{}: `{}` uses a Python interpreter at `{}` which no longer exists",
+                            "hint".cyan().bold(),
+                            command.display_executable(),
+                            python_path.display(),
+                        )?;
+                    }
+                }
+            }
+
+            Err(err)
+        }
+        Err(err) => Err(err),
+    }
+    .with_context(|| format!("Failed to spawn command `{}`", command.display_executable()))?;
 
     run_to_completion(handle).await
 }
diff --git a/crates/uv/src/commands/tool/run.rs b/crates/uv/src/commands/tool/run.rs
index 60e96f3f83974..d28977a3cfc03 100644
--- a/crates/uv/src/commands/tool/run.rs
+++ b/crates/uv/src/commands/tool/run.rs
@@ -58,6 +58,7 @@ use crate::commands::reporters::PythonDownloadReporter;
 use crate::commands::tool::common::{matching_packages, refine_interpreter};
 use crate::commands::tool::{Target, ToolRequest};
 use crate::commands::{diagnostics, project::environment::CachedEnvironment};
+use crate::commands::diagnostics::extract_python_from_shebang;
 use crate::printer::Printer;
 use crate::settings::ResolverInstallerSettings;
 use crate::settings::ResolverSettings;
@@ -433,6 +434,23 @@ pub(crate) async fn run(
                     return Ok(ExitStatus::Failure);
                 }
             }
+
+            // Check if the error is due to a missing Python interpreter in the script's shebang.
+            let script_path = environment.scripts().join(executable);
+            if script_path.exists() {
+                if let Some(python_path) = extract_python_from_shebang(&script_path) {
+                    if !python_path.exists() {
+                        writeln!(
+                            printer.stderr(),
+                            "{}: `{}` uses a Python interpreter at `{}` which no longer exists",
+                            "hint".cyan().bold(),
+                            executable,
+                            python_path.display(),
+                        )?;
+                    }
+                }
+            }
+
             Err(err)
         }
         Err(err) => Err(err),