Hollis-Jefferson was born and raised in Chester, Pennsylvania, the son of Rylanda Hollis, a single mother who worked two jobs as a dietary supervisor and bartender.

[1] He attended Chester High School where he began an outstanding basketball career under head coach Larry Yarbray.

[4] Hollis-Jefferson participated in the 2013 McDonald's All-American Game against future Arizona teammate, Aaron Gordon.

He eventually chose to attend the University of Arizona and represent the school through their successful basketball program over other possibilities such as Florida and Syracuse.

[2] Hollis-Jefferson ended up starting 6 of 38 games played due to the roster that was dominated by the likes of Aaron Gordon, but still got his name on the Pac-12 All-Freshman Team.

[9] He helped lead the Wildcats to two consecutive Elite Eight appearances in the NCAA tournament, losing to Wisconsin on both occasions.

[13] He made his debut for the Nets in their season opener on October 28, 2015, recording eight points and five rebounds off the bench in a 115–100 loss to the Chicago Bulls.

[15] On December 7, he was diagnosed with a non-displaced fracture of the posterior talus in his right ankle, an injury requiring surgery[16] and eight to ten weeks of rehabilitation.

[18] On November 12, 2016, Hollis-Jefferson scored a then career-high 20 points and tied a career high with 13 rebounds in a 122–104 win over the Phoenix Suns.

[20] He strained his right groin during a 116–91 loss to the Milwaukee Bucks on January 26, returning to action on February 26 against the Chicago Bulls after missing the Nets' previous 11 games.

[23] On March 19, 2019, he made a layup with eight-tenths of a second remaining to lift the Nets to a 123–121 win over the Sacramento Kings.

[33] On April 11, 2022, Hollis-Jefferson signed with Atléticos de San Germán of the Baloncesto Superior Nacional.

[40] On July 24, 2023, the Jordan Basketball Federation announced that Hollis-Jefferson had been contracted to play for the national side as a naturalized player.

[42] On August 28, 2023, Hollis-Jefferson drew comparisons to the late Kobe Bryant for his play with the Jordan national team during the 2023 FIBA Basketball World Cup.

[43] The Samahang Basketball ng Pilipinas of the Philippines also offered Hollis-Jefferson to play for their national team but he eventually chose Jordan.