Dead or Alive 5 is the fifth main game in Dead or Alive fighting series. The main story mode takes place two years after the events of Dead or Alive 4. It consists of one-round fights for the different characters with cut-scenes in between. The story is not told in a chronological order, but mixes various characters and events into interconnected chapters. The story is split up in two main storylines, one where Helena Douglas rebuilds a new DOATEC to use its technology for peaceful means and another based around the hunt for Kasumi's evil clone Alpha-152. Characters are generally tied to one of the two storylines, but also interact in some ways.

Next to the main story mode and the bonus missions, the offline fighting mode offers the submodes versus, arcade, time attack and survival. There are both solo and tag team matches. The online mode has simple matches, ranked matches and lobby matches. The training mode is much more extensive than in previous games with detailed strategies for combos, frame data and the ability to adjust the sparring partner's AI. The training mode is also taken online as an online dojo to practice with other players. In the online mode players can host tournaments for up to sixteen players and there is a spectator mode to view matches and chat with other spectators. It is possible to watch match replays, view matches between AI partners and take photographs with a fully controllable camera. The environments contain more destructible elements and there are more details to characters during fights, such as sweat or clothes that get dirty. Stages are still split up in multiple regions where characters can be knocked into Danger Zones. This comes with a new Cliffhanger quick time event where a character has a last chance to not drop down and recover, but the opponent can often inflict even more damage then.

The main fighting mechanics are largely based on Dead or Alive 3. Attacks consist of four buttons (light and strong punches and kicks) to perform combos, throws, blocking. There is no jump input. The game retains the classic rock-paper-scissors-type interruption system where strikes beat throws, throws beat holds, holds beat strikes etc. with additional damage for successful counters. Compared to earlier games the damage for successful counters has been reduced, encouraging more aggressive strategies. Entirely new is the ability to do a full sidestep to dodge incoming attacks, rather than merely re-positioning as in the previous games. There are two other moves that radically change the dynamics. The Critical Burst attack offers a new way to approach stunned opponents. Previously they either needed to be juggled to prevent them from performing a counterhold. Now stunned opponents need to guess between a Critical Burst attack that negates it or a regular launcher. Critical Stuns and Critical Combos are also present. Another novelty is the Power Blow, a powerful, charged attack that can only be accessed after dropping below 50% health.

The game offers 19 recurring characters: Alpha-152, Ayane, Bass, Bayman, Brad, Christie, Eliot, Gen Fu, Hayate, Helena, Hitomi, Jann Lee, Kasumi, Kokoro, Leifang, Lisa, Ryu, Tina and Zack. Two characters are entirely new. Mila is a Spanish female mixed martial arts fighters and Rig is a Canadian taekwondo master. All characters have both Japanese and English voice acting. Three guest characters from the Virtual Fighter series can be unlocked and they also make a cameo appearance in the story mode: Akira, Pai and Sarah.