Her first major role was in the film Mortal Inheritance (1995), where she played a sickle-cell patient who fought for her life against small odds of survival.

[14] Since then, she has starred in several films, including Games Women Play,[15] Blood Sisters,[16] All My Life, Last Wedding, My Story, The Woman in Me and others.

"Ije" was the highest grossing Nollywood film at the time – A feat later broken by Phone Swap (2012).

In 2012, she starred in the Nollywood thriller, Last Flight to Abuja which became the second-highest-grossing movie in West African cinemas in 2012.

[25] In June 2018, Ekeinde and fellow Nigerian Femi Odugbemi received invitations to be voting members at the Academy Awards.

She went to Atlanta, Georgia in the United States to work with producers and songwriters who could help create a sound that would resonate with American audiences.

She had studio sessions with Kendrick Dean, Drumma Boy and Verse Simmonds[30] and recorded a song with singer Bobby V.[31][32] In 2012, Ekeinde also launched a reality television show, Omotola: The Real Me, on Africa Magic Entertainment, a M-Net subsidiary broadcast on DStv.

[33] Ekeinde became a United Nations World Food Programme Ambassador in 2005, going to missions in Sierra- Leone and Liberia.

[34] Her human rights campaign work is centered on her NGO project, called the Omotola Youth Empowerment Program (OYEP).

[38] To promote the 2021 World No Tobacco Day and the #SmokeFreeNollywood campaign, Ekeinde and actors (Dakore Egbuson-Akande, Daniel Effiong, Meg Otanwa, Michelle Dede, Osas Ighodaro pledged to stop smoking in their movie scenes, as it had a negative influence on young kids who looked up to them.

[39] The campaign was backed by US non-profit organization Tobacco-Free Kids and a sub-Saharan public strategy firm - Gatefield.

Others on the list included Shah Rukh Khan, Frank Welker, Bob Bergen, Jack Angel, Mickie McGowan, Michael Papajohn, Martin Klebba, Clint Howard and Chris Ellis.