Meenakshi Seshadri was born into a Tamil family in Sindri, Jharkhand. She is trained in four Indian classical dance forms, namely, Bharata Natyam, Kuchipudi, Kathak and Odissi. She studied dance under Vempati Chinna Satyam and Jaya Rama Rao. She won the Eve's Weekly Miss India contest in 1981 at the age of 17. She represented India at Miss International 1981 held in Tokyo, Japan but did not place. They are descendants of Tamil sangam pandyan kings of atreya gotram and chandra vamsam, meaning lunar race.

Meenakshi Seshadri, born as Shashikala Seshadri, made her debut in the flop film Painter Babu, a 1983 Telugu/Hindi bilingual film opposite Rajiv Goswami, brother of Manoj Kumar. After Painter Babu, Seshadri decided to quit acting. She was encouraged by Subhash Ghai who cast her as his leading lady alongside another newcomer Jackie Shroff in Hero. The film went on to become a blockbuster and Seshadri became an overnight star. She, immediately after the success of Hero, got offers to star with Superstar Rajesh Khanna. She then appeared with Rajesh Khanna in Awara Baap in which she had a double role, but the film underperformed. She then appeared in many commercially unsuccessful films, mainly Love Marriage, Paisa Ye Paisa, and Lover Boy. Her next film Bewafai, again opposite Rajesh Khanna with Rajinikanth in a negative role. The film became one of the highest revenue earning films of the year 1985. This resulted in her gaining a major foothold in the industry. Some of her films were moderately successful, namely Swati, Mera Jawab and Aandhi Toofan. She then appeared in the film Hoshiyar alongside Jeetendra. Subhash Ghai again cast her in his next film Meri Jung, alongside Anil Kapoor, which became one of the highest-grossing films of the year. In the same year she acted with Rajinikanth in Mahaguru as his heroine.

She appeared in many critically acclaimed films in 1986, mainly Swati, a woman-centric art house film, she performed the title role amongst an ensemble cast. The film gained immense critical acclaim and many critics said Meenakshi Seshadri has acted in Swati the way Amitabh Bachchan acts in his films. That same year she appeared in a romantic drama Dahleez alongside Jackie Shroff and Raj Babbar, which dealt with the taboo topic of infidelity, the film though underperformed at the box office. Her other releases that year such as Dilwaala (1986) and Allah Rakha were average performers at the box office. In 1987, she appeared in the hit film Inaam Dus Hazaar alongside Sanjay Dutt. She also appeared in Dacait, an action drama alongside Sunny Deol, it was a commercial failure. In 1988, she appeared in Yash Chopra's Vijay, Seshadri was called the saving grace of the film and Yash Chopra filmed all the songs on her in his trademark use of Switzerland. In 1988, she appeared in Shahenshah alongside Amitabh Bachchan. The film was heavily hyped. After the mega success of Shahenshah, Meenakshi teamed up with Bachchan for films like Toofan, Akayla and Gangaa Jamunaa Saraswati but all three became box office flops. In 1989, she was directed by Dev Anand in the film Sachché Ká Bol-Bálá. In 1989, she made her Tamil film debut with En Rathathin Rathame, which was remake of the Hindi film Mr. India, opposite Bhagyaraj, which bombed at the Box office. In 1989, she appeared in the woman-centric family drama Bade Ghar Ki Beti in the title role and the family drama Gharana and these two films were moderate successes.

She made few appearances on talk shows and rarely gave interviews. In 1987, she appeared in an interview held in London, in which she discussed her personal and professional life.

She acted in many films with Anil kapoor (9 movies), of which two films have an interesting story, Vijay and Inteqam (both released in 1988), in Vijay she does a hot kissing scene with Anil Kapoor in a Fiat car and in Inteqam she tied a Rakhi to Anil Kapoor, the scene was coincidentally filmed in Fiat car too.

In 1990, she appeared in two films of Mahesh Bhatt, first Awaargi, an art house film. Meenakshi's performance was critically acclaimed and many critics call it her best performance, the second film was Jurm, released in the same year. The film was a critical and commercial success. Her role of a wife who has to face problems after her husband gets involved with another woman gained immense critical praise. She received her first nomination for the Filmfare Award for best Actress for her role in the film. She also appeared in the woman-centric film Ghar Ho To Aisa opposite Anil Kapoor, the film was a hit and Seshadri was noted for her comic timing in the film. She then appeared in Ghayal alongside Sunny Deol. This film started her long association with Rajkumar Santoshi. Ghayal was the highest-grossing film of the 1990s and became a blockbuster upon its release. In 1991, she appeared in Akayla, directed by Ramesh Sippy, opposite Amitabh Bachchan, despite being overly hyped, the film flopped at the box office. Her on-screen pairing with Vinod Khanna was widely appreciated, and the pair gave successful films such as Satyamev Jayate, Mahaadev, Jurm, Humshakal and Police Aur Mujrim. She acted in the family drama Ghar Parivar in 1991, with Rajesh Khanna and Rishi Kapoor as her co-stars and the film did very good Business. She made her Telugu film debut with Brahmarishi Vishwamitra in 1991. In 1992, she appeared in the Telugu film Aapad Bandhavudu opposite Cheeranjeevi. In 1992 her film Aaj Ka Goonda Raaj opposite Cheeranjeevi was hit. In 1993, she appeared in the woman-centric film Damini – Lightning. Directed by filmmaker Rajkumar Santoshi, it also starred Rishi Kapoor, Sunny Deol, Amrish Puri, Tinnu Anand, and Paresh Rawal. The film was based on the sensitive subject of injustice towards a rape victim. Damini received a number of awards, including a National Film Award. She was nominated for a Filmfare Award for her role in the film Damini. Her portrayal as Damini was highly praised and she won many accolades for her performance in the film. Damini is regarded as Seshadri's career-defining role.

In 1992 Seshadri featured in a documentary made for television called World of Film: India, the documentary was about the Indian film industry and Seshadri featured with stalwarts such as Shashi Kapoor, Amitabh Bachchan and Mira Nair

She retired from cinema after marrying investment banker Harish Mysore in 1995. She had a civil wedding and a registered marriage in New York too in 1995. The couple has three children, daughter Kendra and sons Josh and Matt. Meenakshi lives in Plano, Texas. There, she teaches Bharatanatyam, Kathak and Odissi. She performs with her students at charity events and fundraisers. A philanthropist, Meenakshi and her students performed at the American Association of Physicians of Indian Origin (AAPI) convention in California.

In 1997 she made a rare public appearance on Shekhar Suman's talk show Movers and Shakers, this was also her last television appearance before she left the industry to raise her children. She discussed her entire career as well as personal life along with her passion for dance and her stage performances.

In 2006 a documentary was made on her life called Meenakshi Accept Her Wings, which was directed by Margret Stephens; the two-hour musical documentary depicted the transitional lifestyle of a dancer-actress to a homemaker. The movie gave a deeper insight to her life after quitting films and her successful marriage.