A large number of hunters are released into Tungmen. One of the hunters bursts into the apartment of Dom’s aunt, Lee Kueiying, killing the latter as the former manages to escape. In response to the bioterror attack, the BSAA seds a Special Operations Unit to kill the hunters and defend any survivors. Unfortunately, the hunters kill all but one member of the BSAA team, Jane Bradstreet, who meets up with Dom. Jane attempts to escort Dom to the extraction point of an incoming BSAA chopper, but both are incapacitated by a stun grenade thrown by an Iron Chariot operative. During this moment, the team of operatives capture Dom and leave the township.
Three months since the attack on Tungmen, a city off the west coast of Canada called Ogilvie suffers a bioterror attack, but this time from B.O.W.s that have never been seen before. The BSAA tracks the source of the attack to a cargo ship and sends Jane, now a Special Operations Agent, to the vessel to investigate. Jane discovers that the ship is computer-steered, and remains hidden on board.
Once the ship docks at its destination island, Jane sneaks her way off the vessel and into the facility that is the source of the B.O.W.s. On her way deeper into the facility, Jane comes across an unoccupied security room and finds Dom in a cell. Disgusted that Dom is being experimented on, Jane decides that rescuing Dom is another priority. Once she figures out exactly where Dom is being held, she immediately goes to his cell, kills the nearby guards, and frees the prisoner. Dom explains to Jane that Charles Burr, the head researcher of the facility, had been using the virus in his blood to develop bioweapons.
The whole facility is soon alerted of Dom's rescue. To prevent their escape, Burr locks down all doors of the building and releases his bioweapons after Dom and Jane. When a handful of lesser bioweapons proves to be unsuccessful, Burr starts to unleash his more powerful creatures, ignoring the fact that doing so is overkill for a mere pair of humans. Regardless, Dom and Jane are able to find weapons strong enough to eliminate these monstrosities, narrowly surviving each encounter. Having no way of leaving the facility, due to the building's doors being locked down, Jane and Dom decide to confront Burr directly. On their way to the control room, they catch a glimpse of an unknown entity who appears to not work for Burr.
The unknown entity Dom and Jane had seen earlier breaks into the control room and shoots all of its occupants, including Burr. The entity then steals a sample of HEV, but Burr injects himself with a special HEV strain he had in his pocket, mutating into a special kind of Draugr, and then tries to stops the thief. His effort is futile, however, and the unknown being escapes. Burr began eating the corpses of his subordinates, using their biomass to mutate even further. Upon entering the control room, Dom and Jane find that Burr had transformed into a centaur-like creature. Not as powerful as his better creations, Burr is inevitably defeated in his struggle to finish off Jane and Dom. While the collapsed Burr is still alive and conscious, Dom mercilessly ignites him with a flamethrower, inducing an agonizing death. Jane then runs to the controls of the building, only to find out that the doors had already been opened. On their way out, Dom and Jane face Burr's ultimate bioweapon – Surtr. Throwing everything they have at the massive bioweapon, Dom and Jane eventually bring it down. Jane tells Dom to follow her to the island's port, hoping that there would be ships remaining.
Even outdoors, bioweapons continue to chase after Jane and Dom, but are unable to prevent them from reaching the docks. As Jane and Dom leave island, the Lyngbakr, yet another one of Burr’s creations, attacks the ship. With the vessel sinking, Jane and Dom board a lifeboat. Well-equipped, the two of them put down the mutated shark. BSAA helicopters arrive a few hours later to extract Jane and Dom, and the latter is then taken into BSAA custody.
While piloting a jet, the unknown entity who infiltrated Jötunheimr is speaking to Albert Wesker, telling the megalomaniac that he had obtained a sample of HEV. Wesker reveals the person's name to be Tony Wesker, who is his fraternal twin brother.
The gameplay of RE:HE is very similar to that of RE5, especially the active gameplay. Just like RE5, the player is dependent on the second player or AI, where many parts of the game require the partner for assistance, such as pulling switches, freeing each other, and reaching otherwise-unreachable platforms. When the player's health drops to 0, he/she will enter a DYING state, which functions exactly the same as it did in RE5; one character must rescue the other. The melee system and the damage scale is also more or less identical to that of RE5. RE:HE also features its own Mercenaries minigame. Unlike RE5, but rather akin to RE6, player characters can move while aiming or readying knives, albeit at a reduced pace compared to running.
Unlike RE5, the game does not feature a merchant/store where the player can purchase and upgrade weapons. All non-character-exclusive weapons within the game must be found in order to be usable. The majority of the firearms in the game also do not feature a laser sight for aiming; in place of the laser is a simple, faint crosshair. Due to the fact that many enemies are very durable, there is a slight aim-assist in which if aim is close enough to a nearby enemy, it will slightly lock on.
The inventory system of RE:HE, although similar, also works differently from that of RE5. A character's inventory features two slots for "primary weapons," two slots for "sidearms," and five additional slots for additional items. Due to the nature of the story, there is no storage system in the game that can be accessed, and the player can only keep whatever weapons he/she ends up with by the end of the level. Because of this, some weapons can be encountered multiple times throughout the story. As in RE5, the player can manually equip the AI partner character before each chapter.
Resident Evil: Hyper-Evolution has three difficulty modes: Normal, Veteran, and Professional. On all difficulties, many enemies are incredibly difficult to kill, but to make up for it, ammunition for even the more powerful weapons is fairly common.
- Main article: Resident Evil: Hyper-Evolution/Weapons
RE:HE takes a more realistic approach on weapons in terms of damage and how they function in real life when compared to other Resident Evil titles. Because of this, several "rules" to weapon stats are included in the game.
Reloading and Capacity
Most weapons will have a different capacity depending on when they are reloaded. These weapons will have one extra bullet if reloaded mid-magazine, but will not have that extra bullet if reloaded before being empty. This is because in many firearms, a shot is loaded into the chamber of the weapon right after the previous shot, unless there is no shot left to be loaded.
Many weapons also reload somewhat more slowly if reloaded after being empty, due to the weapon being needed to be cocked.
The reload times of the shotguns vary depending on how many shots have been fired between reloads, as each shell or round needs to be loaded one at a time.