Making her debut as a child artist in the film Indira (1983), Sen Sharma had her first leading role as an adult in the Bengali thriller Ek Je Aachhe Kanya (2000).

[1][2] Her other notable films during this period include 15 Park Avenue (2005), Dosar (2006), Laaga Chunari Mein Daag (2007), Luck By Chance (2009), Wake Up Sid (2009) and Atithi Tum Kab Jaoge?

[...] Be it her squabbling with the urbane photographer Jehangir Chaudhary or her gently reprimanding him about how her name is pronounced (It's Mee-naa-kshi not Minakshi) or even when she is screaming at her infant, you believe it's Meenakshi you´ve met.

Sen Sharma's performance as a Tamil housewife and her mastery of the accent received universal acclaim and earned her the National Film Award for Best Actress.

The same year, she also starred alongside Waheeda Rehman, Shabana Azmi and Bose in her mother's directorial 15 Park Avenue, which saw her play a mentally-ill woman, which also earned her critical praise, despite the film's commercial failure.

[12] Sen Sharma was next offered the lead role in Mira Nair's Hollywood drama The Namesake (2007), but owing to clashing dates with other films, she could not commit to the project.

Starring an ensemble cast of Ajay Devgn, Kareena Kapoor, Saif Ali Khan, Vivek Oberoi and Bipasha Basu alongside Sen Sharma, the film opened to widespread critical acclaim, with high praise for her performance.

It opened to mixed reviews from critics upon release, however Sen Sharma's performance received praise, thus earning a third nomination for the Filmfare Award for Best Supporting Actress.

Nikhat Kazmi from The Times of India wrote, "Performance-wise, it's the uptight and complex-ridden Sen Sharma who walks away with laurels and laughs even as the film takes a healthy snigger at the desi self.

It opened to widespread critical acclaim upon release, with high praise directed towards Sen Sharma's performance; however, the film emerged as an underwhelming success at the box-office.

The film told the story of a careless rich college brat who is taught the value of owning up to responsibility by an aspiring writer from Kolkata, the latter portrayed by Sen Sharma.

"[31] The New York Times wrote, "Ms. Sen Sharma has made a specialty of characters like Aisha: independent urban women, whose dreams involve careers as well as love.

[33] In June 2009, Sen Sharma starred onstage first time at Atul Kumar's The Blue Mug alongside Rajat Kapoor, Vinay Pathak, Ranvir Shorey and Sheeba Chadha.

[citation needed] In 2010, Sen Sharma starred as a working woman in Ashwani Dheer's comedy Atithi Tum Kab Jaoge alongside Ajay Devgan and Paresh Rawal.

Sen Sharma began 2011 with a special appearance in Vishal Bhardwaj's black comedy 7 Khoon Maaf alongside Priyanka Chopra and Vivaan Shah.

She next appeared in Amitabh Verma's Jackpot opposite Ranvir Shorey,[41] in Suman Mukherjee's adaptation of Shesher Kobita[42] and Goutam Ghose's Shunyo Awnko.

In 2013, she appeared alongside Emraan Hashmi, Kalki Koechlin and Huma Qureshi in Balaji Telefilms' supernatural thriller Ek Thi Daayan, directed by newcomer Kannan Iyer and produced by Vishal Bhardwaj and Ekta Kapoor.

[44] It opened to positive reviews from critics upon release, with Sen Sharma's performance receiving high praise in particular, earning her fourth nomination for the Filmfare Award for Best Supporting Actress.

[48] In 2016, Sharma portrayed a cop in AR Murugadoss' action thriller Akira, alongside Sonakshi Sinha, which received mixed reviews from critics, and emerged as a commercial failure at the box-office.

[49] In 2017, she ventured into film direction with the English-language drama A Death in the Gunj, which starred an ensemble cast including Vikrant Massey and Kalki Koechlin.

[53][54] In 2020, she starred in the comedy-drama Dolly Kitty Aur Woh Chamakte Sitare alongside Bhumi Pednekar as a middle-class woman struggling with societal expectations.

[55] In 2021, her first film appearance was as a woman who loses her father in Seema Pahwa's directorial debut, the ensemble family comedy-drama Ramprasad Ki Tehrvi.

She followed it up with her portrayal of an lower-caste androgynous woman who develops feelings for her colleague in Neeraj Ghaywan's Geeli Pucchi, a segment of the Netflix anthology film Ajeeb Daastaans.

Directed by Nikkhil Advani, the series was set in the emergency room of a government hospital, focusing on the challenges faced by medical staff and first responders during the 2008 Mumbai attacks.

In 2023, her first film appearance was as a hardened cop in the action thriller Kuttey, which received mixed-to-negative reviews from critics upon release, and emerged as a commercial disaster at the box-office.

It received positive reviews upon release, with high praise for Sen Sharma's segment, winning her the Filmfare OTT Award for Best Web Original Film (Critics).