She started her singing career in 1986 when music directors, Kalyanji Anandji gave her chance to sing three songs for the movie Janbaaz. Her first breakthrough came in 1989 when Kalyanji Anandji chose her to sing "Tirchi Topi Wale" for the movie Tridev. The song went to become huge hit year.
She worked with music directors such as Nadeem-Shravan, Jatin Lalit, Anand-Milind, Viju Shah Rajesh Roshan, Anu Malik, A. R. Rahman and singers like Kishore Kumar, Udit Narayan, Kumar Sanu, Abhijeet, Vinod Rathod, Mohammed Aziz, Sonu Nigam, Babul Supriyo, Lucky Ali, Alka Yagnik, Kavita Krishnamurthy, Sadhana Sargam.
In 2006, she came out with an album entitled "Mere Piya", which included several solo performances by herself as well as a duet together with popular singer Sonu Nigam. Lata Mangeshkar was present at the release event. Sapna Mukherjee has done staging live concerts in US, Canada and the UK.