During the early 2000s, he received praise for his performances in Shakti: The Power (2002), Ab Tak Chhappan (2004) and Apaharan (2005); the latter of which earned him his second Filmfare Award for Best Villain, and Taxi No.

Patekar received widespread praise for playing a good-hearted gangster Uday Shetty in the comedy Welcome (2007) and its sequel Welcome Back (2015), and a politician in the political thriller Raajneeti (2010).

He also played notable roles in Aaj Ki Awaz (1984), Ankush (1986), Pratighaat (1987), Andha Yudh (1987), Mohre (1987), Trishagni (1988), Awam (1987) and Sagar Sangam (1988).

He then turned director for his film Prahaar: The Final Attack (1991), co-starring Madhuri Dixit, for which he underwent training for his role as an Indian Army officer.

He co-starred alongside Shah Rukh Khan, Juhi Chawla and Amrita Singh in the romantic comedy Raju Ban Gaya Gentleman (1992) and alongside industry veteran Raaj Kumar in Tirangaa (1993), both of which earned him two consecutive nominations for the Filmfare Award for Best Supporting Actor.

Patekar portrayed a ghost in the children's film Abhay (1994), post which he co-starred with Rishi Kapoor in Hum Dono (1995).

He played a sadist husband in Agni Sakshi (1996), which earned him his second National Film Award for Best Supporting Actor, a deaf father to Manisha Koirala in Khamoshi: The Musical (1996), both of which earned him two nominations for the Filmfare Award for Best Actor, a gangster in Ghulam-E-Mustafa (1997), an honest, but maverick cop in Yeshwant (1997) and a schizophrenic in Wajood (1998).

After a hiatus of a year he returned to acting in Shakti: The Power (2002) in which he played an extremely violent father, which earned him his second nomination for the Filmfare Award for Best Villain.

He starred in several comic roles, one being his highly praised performance in Welcome (2007), which saw him portray a powerful crime lord in Mumbai who once desired to be an actor in films.

He also acted in Prakash Jha's multi-starrer political drama Raajneeti (2010), which earned him his fifth nomination for the Filmfare Award for Best Supporting Actor.

In 2016, he starred as Ganpatrao "Appa" Belwalkar in the film adaptation of the drama Natsamrat which was a major critically and commercial success.

[6] After appearing in It's My Life (2020) and Tadka (2022), in 2023, Patekar headlined Vivek Agnihotri directed The Vaccine War, which tells about the development of Covaxin during the COVID-19 pandemic in India.

Patekar underwent a three-year training to prepare for the movie Prahaar, and worked with General V. K. Singh, who had the rank of Colonel at that time and had a cameo appearance.

[9][10] In late 2018, CINTAA apologized to Dutta admitting that the "chief grievance of sexual harassment wasn't even addressed (in 2008)" but added that since the case was more than three years old, they could not reopen it.

Patekar, choreographer Ganesh Acharya, director Rakesh Sarang and producer Samee Siddiqui were booked for molestation and obscenity under the Indian Penal Code (IPC).

[29][30] In September 2015, Patekar established the Naam Foundation, with fellow Marathi actor Makarand Anaspure, which works to provide aid to farmers overcome by drought conditions in Maharashtra.