diff --git a/crates/uv-cli/src/lib.rs b/crates/uv-cli/src/lib.rs
index 8f77936ad..1ea7b55b1 100644
--- a/crates/uv-cli/src/lib.rs
+++ b/crates/uv-cli/src/lib.rs
@@ -4449,7 +4449,8 @@ pub struct DisplayTreeArgs {
     #[arg(long)]
     pub no_dedupe: bool,
 
-    /// Show the reverse dependencies for the given package. This flag will invert the tree and display the packages that depend on the given package.
+    /// Show the reverse dependencies for the given package. This flag will invert the tree and
+    /// display the packages that depend on the given package.
     #[arg(long, alias = "reverse")]
     pub invert: bool,
 }
@@ -4463,9 +4464,10 @@ pub struct PublishArgs {
     #[arg(default_value = "dist/*")]
     pub files: Vec<String>,
 
-    /// The URL of the upload endpoint.
+    /// The URL of the upload endpoint (not the index URL).
     ///
-    /// Note that this typically differs from the index URL.
+    /// Note that there are typically different URLs for index access (e.g., `https:://.../simple`)
+    /// and index upload.
     ///
     /// Defaults to PyPI's publish URL (<https://upload.pypi.org/legacy/>).
     ///
diff --git a/crates/uv-publish/src/lib.rs b/crates/uv-publish/src/lib.rs
index f85643b03..8a90a8952 100644
--- a/crates/uv-publish/src/lib.rs
+++ b/crates/uv-publish/src/lib.rs
@@ -81,8 +81,12 @@ pub enum PublishSendError {
     ReqwestMiddleware(#[from] reqwest_middleware::Error),
     #[error("Upload failed with status {0}")]
     StatusNoBody(StatusCode, #[source] reqwest::Error),
-    #[error("Upload failed with status code {0}: {1}")]
+    #[error("Upload failed with status code {0}. Server says: {1}")]
     Status(StatusCode, String),
+    #[error("POST requests are not supported by the endpoint, are you using the simple index URL instead of the upload URL?")]
+    MethodNotAllowedNoBody,
+    #[error("POST requests are not supported by the endpoint, are you using the simple index URL instead of the upload URL? Server says: {0}")]
+    MethodNotAllowed(String),
     /// The registry returned a "403 Forbidden".
     #[error("Permission denied (status code {0}): {1}")]
     PermissionDenied(StatusCode, String),
@@ -577,18 +581,32 @@ async fn handle_response(registry: &Url, response: Response) -> Result<bool, Pub
         .get(reqwest::header::CONTENT_TYPE)
         .and_then(|content_type| content_type.to_str().ok())
         .map(ToString::to_string);
-    let upload_error = response
-        .bytes()
-        .await
-        .map_err(|err| PublishSendError::StatusNoBody(status_code, err))?;
+    let upload_error = response.bytes().await.map_err(|err| {
+        if status_code == StatusCode::METHOD_NOT_ALLOWED {
+            PublishSendError::MethodNotAllowedNoBody
+        } else {
+            PublishSendError::StatusNoBody(status_code, err)
+        }
+    })?;
     let upload_error = String::from_utf8_lossy(&upload_error);
 
-    trace!("Response content for non-200 for {registry}: {upload_error}");
+    trace!("Response content for non-200 response for {registry}: {upload_error}");
 
     debug!("Upload error response: {upload_error}");
+
+    // That's most likely the simple index URL, not the upload URL.
+    if status_code == StatusCode::METHOD_NOT_ALLOWED {
+        return Err(PublishSendError::MethodNotAllowed(
+            PublishSendError::extract_error_message(
+                upload_error.to_string(),
+                content_type.as_deref(),
+            ),
+        ));
+    }
+
     // Detect existing file errors the way twine does.
     // https://github.com/pypa/twine/blob/c512bbf166ac38239e58545a39155285f8747a7b/twine/commands/upload.py#L34-L72
-    if status_code == 403 {
+    if status_code == StatusCode::FORBIDDEN {
         if upload_error.contains("overwrite artifact") {
             // Artifactory (https://jfrog.com/artifactory/)
             Ok(false)
@@ -601,10 +619,10 @@ async fn handle_response(registry: &Url, response: Response) -> Result<bool, Pub
                 ),
             ))
         }
-    } else if status_code == 409 {
+    } else if status_code == StatusCode::CONFLICT {
         // conflict, pypiserver (https://pypi.org/project/pypiserver)
         Ok(false)
-    } else if status_code == 400
+    } else if status_code == StatusCode::BAD_REQUEST
         && (upload_error.contains("updating asset") || upload_error.contains("already been taken"))
     {
         // Nexus Repository OSS (https://www.sonatype.com/nexus-repository-oss)
diff --git a/docs/reference/cli.md b/docs/reference/cli.md
index ae61828ed..73a4678fe 100644
--- a/docs/reference/cli.md
+++ b/docs/reference/cli.md
@@ -7214,9 +7214,9 @@ uv publish [OPTIONS] [FILES]...
 
 <p>This setting has no effect when used in the <code>uv pip</code> interface.</p>
 
-</dd><dt><code>--publish-url</code> <i>publish-url</i></dt><dd><p>The URL of the upload endpoint.</p>
+</dd><dt><code>--publish-url</code> <i>publish-url</i></dt><dd><p>The URL of the upload endpoint (not the index URL).</p>
 
-<p>Note that this typically differs from the index URL.</p>
+<p>Note that there are typically different URLs for index access (e.g., <code>https:://.../simple</code>) and index upload.</p>
 
 <p>Defaults to PyPI&#8217;s publish URL (&lt;https://upload.pypi.org/legacy/&gt;).</p>