He then directed a remake of the 1978 Amitabh Bachchan film, Don titled Don - The Chase Begins Again which starred Shahrukh Khan in the title role. The film released on 20 October 2006. Though the movie was critically hammered, it proved to be a great success at the box office, grossing over 50 crores, and being the fifth biggest hit of the year. In 2007 he produced the film Honeymoon Travels Pvt. Ltd. which performed fairly well at the box office.

In 2007, he directed Positive, a 12-minute short film on HIV stigma and the need for family support for the patient. Shot in Mumbai, it was part of 'AIDS JaaGo' (AIDS Awake), a series of four short films, directed by Mira Nair, Santosh Sivan, Vishal Bhardwaj and Farhan Akhtar, in a joint initiative of Mira Nair's Mirabai Films and voluntary organisations Avahan and the Bill & Melinda Gates Foundation. The film stars, Boman Irani, Shabana Azmi and a debutant actor, Arjun Mathur.

In 2008, Akhtar made his acting debut in Rock On!. It was critically acclaimed as well as a box office hit, doing exceptionally well particularly in the metros. He also appeared as the male lead in his sister Zoya's directorial debut, Luck By Chance. His latest film is Kartik Calling Kartik. Two more movies are scheduled to release in 2010: Dhruv and Gulel (his only acting venture which is not his production too).In 2011 Zindagi Na Milegi Dobara is scheduled to release in which he co-stars with Hrithik Roshan.

Akhtar also made his singing debut in Rock On!, singing in most of the movie's songs. He was even supposed to sing a song for Blue, which has music by A. R. Rahman. However this could not happen as Akhtar was shooting for Kartik Calling Karthik then and could not find the time.

He has appeared as a judge on a few shows on television, including the first season of the dance-reality show, Nach Baliye (2005), and the beauty pageant, Femina Miss India (in 2002). He also hosted a TV show on NDTV Imagine, called Oye! It's Friday!.