On March 10, 2014, Zhilei Zhang announced that he would be turning professional in boxing. He signed a promotional agreement with Dynasty Boxing, a promotional firm specializing in the Chinese market.
In his pro debut on August 8, 2014, in Fallon, Nevada, Zhang knocked out Curtis Tate in the first 17 seconds of the first round.
Zhang went on to compile a perfect record of 20-0 before facing Andriy Rudenko in Monaco on November 30, 2019. He dominated Rudenko and secured a convincing unanimous decision victory, winning on all three scorecards.
On November 7, 2020, Zhang fought Devin Vargas on the undercard of the WBC lightweight title fight between Devin Haney and Yuriorkis Gamboa. It was his debut as a Matchroom Boxing fighter, and Zhang dropped and stopped Vargas in the fourth round.
Returning to the ring on February 27, 2021, Zhang faced journeyman Jerry Forrest on the undercard of the super-middleweight title fight between Canelo Álvarez and Avni Yıldırım. Zhang started strong, scoring three knockdowns in the opening three rounds, but Forrest managed to battle back and the fight ended in a majority draw. Zhang was later hospitalized and diagnosed with anemia, high enzyme levels, and low-level renal failure, potentially caused by severe dehydration.
On November 27, 2021, Zhang fought Craig Lewis on the undercard of Teófimo López vs. George Kambosos Jr. Zhang started slowly but dropped Lewis twice in the second round, leading to Lewis’ corner throwing in the towel and giving Zhang a TKO victory.
Zhang was scheduled to fight Filip Hrgović in an IBF title eliminator on May 7, 2022, but Hrgović withdrew from the fight due to the death of his father. Scott Alexander was chosen as a replacement, and Zhang won the bout via first-round knockout on the Canelo Álvarez vs. Dmitry Bivol undercard.
The fight against Hrgović was rescheduled for August 20, 2022, in Jeddah, Saudi Arabia, on the undercard of Oleksandr Usyk vs. Anthony Joshua II. Zhang knocked down Hrgović in the first round but ultimately lost a close-fought battle over twelve rounds. The judges awarded the fight to Hrgović with scores of 115-112 (twice) and 114-113. The decision was considered generous by broadcaster Sky Sports and Hrgović’s performance was described as bizarre.