The two women will headline an MF & DAZN: X Series 15 card in Houston, USA.
Brook captured the middleweight title with a spectacular stoppage win over AJ Bunker earlier this year.
The challenge will be even tougher this time around as the British star takes on mixed martial arts veteran VanZant.
The American boasts an 8-5 record in professional mixed martial arts and has competed in nine UFC bouts.
She last appeared in the cage in July 2020, losing in the first round to Amanda Rivas.
The co-main event will feature former NFL player Le'Veon Bell facing Tristan Hamm in the opening quarterfinals of the MFB Cruiserweight Championship tournament.
“X Series 15 will go down in history as the night that took the women's division across the crossover boxing world to a whole new level,” said Misfits Boxing co-president Momz Taylor.
“Misfits Boxing Women's Middleweight Champion Elle Brook has accepted the biggest challenge of her life yet, facing former UFC and BKFC powerhouse Paige VanZant.
“This is a phenomenal matchup and we can't wait until May 25th as it will be another landmark night for X Series.”
The show will begin at 7pm EST, 12am BST, with the main event ring walk scheduled for approximately 11pm EST, 4am BST.
Fans can watch the match live on DAZN.
MF & DAZN: X Series 15 full card
MFB Women's Middleweight Championship
Elle Brook vs. Paige VanZant
Middleweight bout
Okemuka Zivnor vs Brendan Kelly
Light Heavyweight Bout
Le'Veon Bell vs Tristan Hamm
Lightweight bout
Li Mu vs Elijah Smith
Super Middleweight Bout
Jeremy Park vs Anthony Vargas
Women's Welterweight Bout
Alana Potocznik vs Lauren Baker
Women's Welterweight Bout
Alicia Magen vs Jessica Duban
Super Flyweight Bout
Bi Nguyen vs Silvia Fernandez
game
Oscar Perez vs Rafael Reyes
