The formation of the body was announced in June by Boris Johnson in wake of anti-racism protests following the death of George Floyd.
It will look at all aspects of inequality, including criminal justice, education, employment and health.
Mr Sewell said the commission would “seek to inform a national conversation about race, led by the evidence”.
Now the boss of education charity Generating Genius, Mr Sewell worked with the PM in 2013 when he was Mayor of London, leading his education inquiry into the capital’s schools.
The prime minister said Mr Sewell shared his “commitment to maximising opportunity for all”.
The commission will report back directly to Mr Johnson with its findings by the end of the year.
As well leading a charity, Mr Sewell has been a board member for both the Science Museum and the Youth Justice Board.
He is also a columnist, author and fellow at University College London, and sat on the Windrush working group.
He is a longstanding commentator on racial issues and education, attracting criticism from some quarters for his views, such as claiming boys were being failed by schools because lessons had become too “feminised”.
He also said an anti-intellectual Afro-Caribbean youth culture was one of the reasons girls performed better than boys in school.
After the appointment was confirmed, Mr Sewell said: “I have spent my entire career in education striving to help all students achieve their full potential.
“I know however that inequality exists, and I am committed to working with my fellow commissioners to understand why.”