set_post_thumbnail() │ WP 3.1.0

/*
 * $file is the path to your uploaded file (for example as set in the $_FILE posted file array)
 * $filename is the name of the file
 * first we need to upload the file into the wp upload folder.
 */
$upload_file = wp_upload_bits( $filename, null, @file_get_contents( $file ) );

if( ! $upload_file['error'] ){
	// if succesfull insert the new file into the media 
	// library (create a new attachment post type).
	$wp_filetype = wp_check_filetype( $filename, null );

	$attachment = [
		'post_mime_type' => $wp_filetype['type'],
		'post_parent'    => $post_id,
		'post_title'     => preg_replace( '/\.[^.]+$/', '', $filename ),
		'post_content'   => '',
		'post_status'    => 'inherit',
	];

	$attachment_id = wp_insert_attachment( $attachment, $upload_file['file'], $post_id );

	if( ! is_wp_error( $attachment_id ) ){
		// if attachment post was successfully created, insert it as a thumbnail to the post $post_id.
		require_once( ABSPATH . "wp-admin" . '/includes/image.php' );

		$attachment_data = wp_generate_attachment_metadata( $attachment_id, $upload_file['file'] );

		wp_update_attachment_metadata( $attachment_id, $attachment_data );
		set_post_thumbnail( $post_id, $attachment_id );
	}
}

Let's say we want to set a thumbnail for post with ID=56. We know the ID of the media file (attachment) - it is 89:

$post_id = 56;
$attach_id = 89;
$set_thumb = set_post_thumbnail( $post_id, $attach_id );

if( $set_thumb )
	echo 'The miniature is set.';
else
	echo 'The thumbnail has been deleted.';

This code will automatically put a thumbnail of the post when you save it. If the post has no thumbnail.

The first picture attached to the post will be grabbed.

add_action( 'future_to_publish', 'autoset_featured' );
add_action( 'draft_to_publish', 'autoset_featured' );
add_action( 'new_to_publish', 'autoset_featured' );
add_action( 'pending_to_publish', 'autoset_featured' );
//add_action( 'the_post', 'autoset_featured' );
add_action( 'save_post', 'autoset_featured' );

function autoset_featured() {
	global $post;

	// check for a post thumbnail
	if( has_post_thumbnail( $post->ID ) )
		return;

	$attached_image = get_children( [
		'post_parent'    => $post->ID, 
		'post_type'      => 'attachment', 
		'post_mime_type' => 'image', 
		'numberposts'    => 1, 
		'order'          => 'ASC',
	] );

	// make a condition to check for a picture
	if( $attached_image ){
		foreach( $attached_image as $attachment_id => $attachment ){
			set_post_thumbnail($post->ID, $attachment_id);
		}
	}
}