Manjari Fadnis was first seen on television during the second season of the Indian version of the singing reality show Popstars, which was aired on Channel [v] India in 2003. 

She started her film career with Rok Sako To Rok Lo in 2004, but her big break was Jaane Tu... Ya Jaane Na (2008) as the lead actor's girlfriend, for which she won a Stardust Award for Breakthrough Performance-Female 2009. She then starred in the Walt Disney-produced superhero film Zokkomon, starring Darsheel Safary in the titular role. The film received positive reviews from critics. She also worked in the Telugu film Shakti (2011) alongside Jr. NTR , and later, in a Hindi film I M 24 (2012) and her debut Kannada film Munjane (2012).The year 2013 saw release of her films Warning, a 3D underwater film and Grand Masti (opposite Aftab Shivdasani). Grand Masti was the highest grossing Bollywood film with an A (Adults Only) certificate in India. Her next film was Mohanlal starred Mr. Fraud (2014), which marked her Malayalam debut. Then came her romantic comedy film Kis Kisko Pyaar Karoon (2015) starring Kapil Sharma. The film was a box office success.She then acted alongside Shreyas Talpade in the content driven film Wah Taj (2016). The movie had a dance song "Chori Chichori" for which Fadnis attired as traditional Marathi Mulgi did a semi-folk popular dance.She also worked in her maiden Marathi film Sarv Mangal Savdhan (2016) opposite Raqesh Vashisth. She appeared as a lead actress in the inspirational film Jeena Isi Ka Naam Hai (2017) starring Arbaaz Khan, Himansh Kohli and Ashutosh Rana, set in exotic locations.In 2018, she came up with a murder mystery film Nirdosh opposite Ashmit Patel and an action comedy film Baa Baaa Black Sheep opposite Manish Paul.

In 2019, she appeared in an Amit Sadh starred thriller web-film Barot House aired on ZEE5.

In 2017, her short film Khamakha (2016) won the Filmfare for Best Short Film People's Choice Award. Her other short films are The Morning After (2013), The Cot (2017), Jackie Shroff starred The Playboy Mr Sawhney ( 2018 ) and Interdependence : Megha's divorce (2019).

In 2019, she appeared in a web series Fuh se Fantasy:The Blindfold on Voot.[30][31]

She made her first theatrical performance Double Deal Reloaded (English), in Mumbai in 2017 and the following year in Kolkata, Bengaluru and Hyderabad. In 2018, she came up with a musical drama Devdas staged at Mumbai.

She has undergone dance training under Shiamak Davar and vocal training under Sucheta Bhattacharjee.

She received the Movers and Shakers award at the MAAC 24FPS International Animation Awards 2015.