Akhtar, after establishing a production company named Excel Entertainment along with Ritesh Sidhwani, made his directorial debut with Dil Chahta Hai (2001) and received critical acclaim for portraying modern youth. The film also won a National award. Following it, he made Lakshya (2004) and had his Hollywood debut through the soundtrack of Bride and Prejudice (2004), for which he wrote the lyrics. He went on to make the commercially successful Don (2006). He directed a short-film titled Positive (2007) to spread awareness on HIV-AIDS.
He started his acting career with Rock On (2008), for which he won a second National Award for Best Feature Film in Hindi as producer, and indulged in further experimentation before he acted in, produced and wrote the dialogues for the critical and commercial success Zindagi Na Milegi Dobara (2011), which won him two Filmfare Awards, including Best Supporting Actor. In the same year, he directed a sequel to Don titled Don 2 (2011), which remains as his highest-grossing film till date. He achieved further success by portraying Milkha Singh in the 2013 film Bhaag Milkha Bhaag, earning him the Filmfare Award for Best Actor. In 2016, Akhtar received praise for starring in the crime thriller Wazir and the comedy drama Dil Dhadakne Do.