At the end of previous season, contracts expired with four players: Marko Jagodić-Kuridža, Jordan Loyd, Landry Nnoko and Duop Reath.

An American guard Jordan Loyd, who was the team's best scorer in the previous season's runs in Adriatic League and EuroLeague, was first to leave the club on 14 June 2021 after signing two years contract with Russian side Zenit Saint Petersburg.

The first two signings of the season were Montenegrin international guard Nikola Ivanović and Serbian forward Luka Mitrović who already played for the club and was the Zvezda's captain during his first spell between 2012 and 2017.

American guard Langston Hall left for the Turkish side Bahçeşehir Koleji after early termination of his contract with Crvena zvezda.

Highlights of his career were Euroleague title with Fenerbahçe in 2017 and silver medals with Serbia in 2014 World Cup and 2016 Summer Olympics.

[16] On 19 July 2021, Australian international big man Duop Reath left the club after his one-year contract expired.

[30] On 23 September 2021, Serbian power forward Nemanja Popović signed three-years long contract with the club.

In his first official game for Crvena zvezda, Nikola Ivanović won the MVP of the round honour after erupting for 20 points, 6 rebounds, 6 assists, 4 steals and a valuation of 35.

Although club had limited squad of only 8 available players due to multiple injuries they managed to battle to a close defeat of 61–57.

In Euroleague club opened the month with 2 home wins against Panathinaikos and ASVEL, followed by the 3 defeats against Baskonia, Real Madrid and UNICS.

In Adriatic league club played 4 games and won them all, including the match against their rivals Partizan NIS.

On 8 November 2021, Serbian former international guard Stefan Marković signed two years contract with the Crvena zvezda.

The club was sanctioned with two fines (total of 11,000 euros) for conduct of a group of people committing acts that show a lack of respect and for the throwing of objects onto the court during the EuroLeague Round 15 home game against FC Barcelona on 14 December.

Additionally, the club was sanctioned with two fines (total of 38,000 euros) for the aggression against a visiting team player, and for the throwing of objects onto the court during the EuroLeague Round 16 home game against FC Bayern Munich, two days later.

[46][47][48] Also, the ABA League Round 15 road game against Budućnost VOLI scheduled to be played on 9 January was officially postponed due to COVID-19 outbreaks in both Budućnost and Crvena zvezda teams[49] as well as ABA League Round 16 home game between Crvena zvezda and Igokea m:tel that was originally scheduled for 17 January.

That extended club's winning record in this season to 13 games and won them second place in the league at the end of the month.

Crvena zvezda won both of them, against Mega Mozzart and Zadar thus increasing their unbeaten run to 15 games in a row.

The club eliminated Radnički Kragujevac in a quarterfinal, Mega Mozzart in a semifinal and won their 11th national cup title by beating Partizan in the final.

An American point guard Nate Wolters received the Radivoj Korać Cup MVP Award.

In the Adriatic League, the club played four games, winning three and losing the eternal derby against Partizan NIS.

At 16 years, seven months, and eighteen days of age, he became the youngest player in club's history to score points for Crvena zvezda in the regional league.

In Adriatic league club won their last four regular season games, clinching top seed for the playoffs and direct qualification for the semifinals in which they will play against Slovenian side Cedevita Olimpija.

Nikola Kalinić was named both regular season MVP[58] and member of Ideal Starting Five,[59] while Branko Lazić received Best Defender award.

[61] Guard Nate Walters went to the U.S. upon the club's approval on personal matters and won't be in the roster for the upcoming Serbian League Playoffs.

[63][64] On 16 June, guard Luka Vudragović and forward Lazar Đoković officially signed their first professional agreements.

[65][66] On 11 September 2021, forward Aaron White broke the left forearm after falling following a dunk during a preseason game against Panathinaikos OPAP.

The following day the Zvezda announced that White will undergo surgery on Sunday in Munich and that usual recovery is about six weeks.

[67][68][69] The club canceled two preseason games in September 2021 due to multiple injury reports (Dejan Davidovac, Branko Lazić, Nate Wolters, Ognjen Dobrić, and Marko Simonović).

[72] Two day later, 11 more players and staff members were tested positive for the COVID-19, including head coach Dejan Radonjić, his assistants Goran Bošković and Nikola Birač, and players Branko Lazić, Luka Mitrović, Austin Hollins, Nate Wolters, Ognjen Dobrić, Stefan Marković, Marko Simonović, and Maik Zirbes.

[89] Two days prior the trip to Greece, the club canceled last two games due to multiple injury reports.