Players in Hong Kong realised they could dress up as protesters after a new update for the game was released earlier this month.
They spread the word on LIHKG - which has been called the Hong Kong version of social news site Reddit - and started organising violent expeditions.
Mainland players responded by showing up dressed as riot police with water cannon trucks.
Hong Kong-based news site Abacus was one of the first to report the development.
The Hong Kong protests started in June over a controversial extradition bill, and have now evolved into broader anti-government demonstrations.
GTA V is set in the fictional city of Los Santos, which is based on Los Angeles.
But that has not stopped gamers in mainland China and Hong Kong from using it as a battleground.
The latest version of GTA V's Diamond Casino Heist update saw more clothing items added to the game including yellow hard hats and gas masks.
On LIHKG, players were telling each other how to buy a set of clothing they have nicknamed "Glory to Hong Kong" and to join a "crew" called "Stand With Hong Kong".
The crew has been wreaking havoc in the game, trashing subway stations and attacking police vehicles with petrol bombs.
The two sides ended up in an "epic" fight in the game, according to social media discussions on Weibo. The mainland gamers won as they had more players on their side.
GTA V has not been approved by mainland Chinese authorities as it contains drugs, violence, and scenes of a sexual nature.
However, the game can be downloaded on the Steam gaming store and accessed through a number of other loopholes.
Gamers have been able to play out the Hong Kong protests on a number of other titles over the last few months.
A group of Hong Kong activists developed a virtual reality game called Liberate Hong Kong that allowed people to "experience" the protests without leaving their home.
There was also an Android game called The Revolution of Our Times, but Google removed it from the Play Store
Rockstar Games, the gaming company behind GTA V, did not immediately respond to a request for comment.
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