Duke Nukem Forever has 4 basic multiplayer modes. 3 more multiplayer modes are added by purchasing the DLC. There can be up to 8 players on the server, in team modes divided on two four-man teams (blue and red, distinguished primarily by the colours of their tops and also by some minor details, like gloves or tripmine laser colours). The basic gamemodes are:
- Dukematch - players compete for their own score. Each kill adds 1 point to the killer's score, while suicides do not take the points back, as it was in Duke Nukem 3D. Player who has most points when the time runs out or who scores enough points to fulfill the limit set by the host wins. In case of a draw between two or more players, there is an overtime of 60 seconds. The draw happens always when two highest ranking players have the same score when the time runs out, even if their deathcount is different.
- Team Dukematch - players are divided into two teams. To score they have to kill enemy team members. There is no friendly fire, as is with all the multiplayer modes. Players can usually change the team they play in during the play, but it is generally seen as cowardish behaviour to join the winning team during last seconds of a round. By default, players are assigned into each team along the pattern blue-red-red-blue-blue-red-red-blue.
- Capture the Babe - capture the flag with a Duke twist. Players have to kidnap the other team's Holsom twin and bring her to their own base while also defending their own babe from being captured. However, player who has stolen the babe cannot run or crouch and can only use the garter pistol. Also, the player carrying the babe will get killed with a single shrinker shot. When the babe is dropped, players of the defending team can teleport her back to base by simply touching her or she will be teleported automatically after 10 seconds. This gamemode suffers most from too few players or uneven teams. It cannot be played on every map.
- Hail to the King - in this gamemodes, teams score points by standing inside the control point, which is a giant radioactive symbol that spawns on the floor across the map. The more teammates that are in control point together, the faster they will score - however, they also have to defend the control point from the enemy team to score. The control point changes its position every minute. Depending on the map, the number of control point locations vary from 4 to 6.
The additional gamemodes available in the DLC are:
- Hail to the King Free for All - the point of the game is same like with normal HTTK, however this time there are no team - everyone scores for their own. The notable difference is that points are scored faster than in team version.
- Freeze Tag - players are divided into two teams and equipped only in Freeze Rays. The goal is to freeze the entire enemy team, as it will make them all shatter at once and multiply the points by 3. In this gamemode, players should stick together for maximum firepower. The game also suffers badly from uneven teams, as the smaller team will be a lot easier to freeze.
- Hot Potato - in this gamemode, players have to grab the babe and hold onto her for the longest time to score points, everyone for their own. The player who holds the babe is, again, limited like in CTB. Also, the babes position is revealed by a marker on screen, so the player who is scoring will attract most fire from other players. After the babe is dropped and not picked up in 10 seconds, she will spawn in a random place across the map. It cannot be played on every map.