Enemies will spawn on the world map whenever an enemy icon is revealed on a tile. When all player characters have taken their turns, one or more enemy types may activate, causing those enemies to move towards the closest player character. Enemies also prevent player characters from performing encounters or quests when in the same tile as them. If an enemy is in the same tile as a player character when they activate, the enemy will attack them.
When fighting an enemy, the player character must roll three VATS dice, each side of which highlights at least one body part and has up to two vault icons. If the body parts highlighted match the enemy's vulnerabilities, they are hit and, if the number of hits is equal to or greater than the enemy's level, they will die. For each vault icon shown on the dice, the player character will receive damage equal to the enemy's level. VATS dice can be rerolled based off the stats of the weapon they have equipped.
Each enemy also has up to two of the following abilities:
Aggressive - this enemy automatically attacks any player character within attack range.
Armor - this enemy takes one more point of damage to kill.
Caps - When killed, this enemy drops a number of bottle caps equal to their level.
Fast - When activated, this enemy moves up to two times instead of one.
Loot - this enemy allows the player character to draw a loot card after killing it.
Radiation - this enemy deals radiation damage equal to its level when damaging a player character.
Ranged - this enemy can attack player characters in adjacent spaces and deals extra damage to those without ranged weapons.
Retreat - this enemy becomes inactive if the player character fails to kill it and can't be targeted until the next time its type activates.
Faction enemies only appear in specific scenarios. If a player character declares loyalty to the enemy's faction, that enemy will ignore the player character and not attack them. Faction enemies will also become more powerful as their faction gains in power, potentially increasing their level or giving them different abilities.