Wealthy socialite Charlotte Cartwright (Kathy Bates) and her dear friend Alice Pratt (Alfre Woodard), a working class woman of high ideals, have enjoyed a lasting friendship throughout many years. Suddenly, their lives become mired in turmoil as their adult children's extramarital affairs, unethical business practices and a dark paternity secret threaten to derail family fortunes and unravel the lives of all involved. Alice's self-centered newlywed daughter Andrea (Sanaa Lathan) is betraying her trusting husband Chris (Rockmond Dunbar) by engaging in a torrid affair with her boss and mother's best friend's son William (Cole Hauser). While cheating on his wife Jillian (Kadee Strickland) with a string of ongoing dalliances with his mistress Andrea, William's true focus is to replace the COO of his mother's lucrative construction corporation. Meanwhile, Alice's other daughter Pam (Taraji Henson), a kind but no nonsense woman married to a hard working construction worker (Tyler Perry), tries to steer the family in a more positive direction.

While paternity secrets, marital infidelity, greed and unsavory business dealings threaten to derail both families, Charlotte and Alice decide to take a breather from it all by making a cross-country road trip in which they rediscover themselves and possibly find a way to save their families from ruin in Tyler Perry's The Family That Preys.