The 49-year-old will play a nurse with a troubled past who returns to Chicago after working in Indonesia on tsunami relief.
According to The Hollywood Reporter, her arrival in the second episode "promises to shake County General's ER to the core".
Executive producer John Wells said: "Angela is a wonderfully talented actress whom I've long hoped to work with."
Noah Wyle is to reprise his role as John Carter in at least four episodes of the NBC show, which will bow out next February after 15 years.
Bassett was nominated for an Oscar for her portrayal of Tina Turner in 1993 movie What's Love Got to Do with It. ER will be her first full-time role in a TV series.
> 'ER' star backs decision to end show