Fatigue is a measurement of how much of a special type of damage (Fatigue damage) a character can take before they are knocked down in a state resembling unconsciousness.
If a creature or NPC suffers enough Fatigue damage to reduce their Fatigue level to 0 or below, the value is immediately set to -30 and the NPC will enter a state similar to unconsciousness. While in this state the NPC cannot move or react, but is still considered alive and can suffer normal damage, up to death. Unlike unconsciousness in Fallout 3, "fatigued" or "knocked out" NPCs cannot be looted; any attempts to interact with them will fail with the message "<NAME> is Unconscious".
Fatigue is a "self-restoring" value, in the sense that it restores back to its maximum value over time. If an NPC suffers Fatigue damage, their Fatigue value will slowly raise at a rate of one point per second until it is back at its maximum. Fatigue maximums range from 50 (low-level creatures such as mole rats) to 910 (Legate Lanius). Though fatigue values are modified by the NPC's Endurance and Level, the value is derived from a "base" Fatigue value, set individually for each NPC or creature. The approximate average Fatigue rating for humanoid NPCs is 250.
Once the Fatigue value of an NPC dips below 0 it is immediately set to -30. From this point it will increase at a rate of one point per second. Additional Fatigue damage can be applied to a "Fatigued out" NPC, but it cannot lower the value below -30. Once the NPCs Fatigue level climbs back to 0 they will become responsive again, and the NPC's Fatigue level will be restored to its maximum value.
In plain terms, this means that for every level the NPC's Fatigue rating is increased by 10 and for every point of Endurance the rating is increased by 20.
Within Fallout 3, Fatigue damage is only encountered as part of the "capture" sequence at the end of the quest Finding the Garden of Eden when the Lone Wanderer and their companions are incapacitated. Nonetheless, the game's engine does support Fatigue damage.
In Fallout: New Vegas the number of sources which induce Fatigue damage are limited. Only five weapons inherently cause Fatigue damage: boxing gloves, boxing tape, cattle prod, flash bangs, and Golden Gloves. All shotguns chambered for the 12 gauge shell can also cause Fatigue damage if loaded with 12 gauge bean bag ammunition.
Most sources of Fatigue damage make exceptions for robots and the Courier, as neither should ever be rendered fully unconscious. In these cases a small amount of additional standard damage is applied to the target instead. The only exceptions are flash bangs and 12 gauge bean bag rounds, which due to various bugs do not properly account for robots or the player.