NBA 2K16 is the 17th main game in the annual NBA 2K series of basketball games. It is based on the 2015-2016 NBA season and features all of its competing teams as well as classic teams (including twelve new ones such as the 1999–2000 Toronto Raptors) and 25 European teams competing in the Euroleague. The basic gameplay works like in previous iterations but with some changes both in presentation and gameplay. This include upgraded player models and new animations, more realistic ball and rim physics and player collisions. Changes in controls include dedicated buttons for lobs and bounce passes. In addition to playing individual exhibition matches there are numerous other game modes such as MyCareer, MyGM, MyLeague and MyTeam.

The MyCareer mode is called Livin' Da Dream and was developed in association with film maker Spike Lee. It is designed to be more story oriented and cinematic than previous games' career modes and sees the player taking control of a young basketball player from Harlem called Frequency Vibrations ("Freq"). Freq starts out in a small high school team but as the story progresses he will move first to a college team and later the NBA. The ultimate goal is to become one of the greatest players of all time. Before starting out it is possible to customize the appearance of the player and to choose a position and scoring style. Games in the career modes only involve controlling one player with the others being AI driven. Between games the player has access to his own customizable court where he can upgrade his character or practice playing the game. It's also possible to invite online friends to private games. In addition to playing the games the career mode also involves making choices off the court while interacting with other players, coaches, media and fans.

The MyGM mode allows the player to become the general manager of a team. This means the player has access to all aspects of the game including signing and trading players, negotiating contracts with both players and coaches, interacting with the team owner as well as media, building facilities and many other managerial tasks. New to this edition is the ability to move the team to a new city, summer leagues, three team trades and the ability to customize arenas and jerseys. The MyLeague mode is similar to MyGM but removes certain restrictions to make the game more flexible with more customization options. Whereas MyGM is an offline mode, MyLeague features various online components. The MyTeam mode involves building a team by collecting trading cards. By collecting cards players, playbooks and other items can be unlocked. Cards are bought with virtual currency and come in packs with a random selection of items. They have different levels indicating how good they are with bronze cards being cheaper, while gold cards are of higher quality.