Various humans will fight Crypto on sight, in addition to human civilians who merely run away. A majority of the time, the enemies you may face are mostly determined by the Alert Level. The Alert Level is located on the upper part of the screen and it shows how alert the humans are. The more chaos Crypto creates, the higher the Alert Level will be. There are four levels: Warning (blue), Police (yellow), Military (orange), and Majestic (red).
- Non-combatants: These humans wield no weapons (although female civilians in Santa Modesta and Capitol City will warn Crypto that they have pepper spray or a mace when he follows them while holobobbing), and will run and hide when they see Crypto or his saucer in the air; they will just walk past it when it has landed on the ground. Non-combatants are split into 4 categories: civilians, crazies, politicians, and scientists, in ascending order of the amount of DNA they have.
- Farmers: Farmers walk around Turnipseed Farm and Rockwell, carrying their shotguns everywhere they go. They will shoot at Crypto on sight. They are the weakest of the enemies. Although they are considered enemies, they appear as civilians on the mini-map. Cortex scans reveal them to be stupid, often with an odd "love" of their farm animals, and occasionally singing the Howdy Doody theme song. They often call crypto "space man."
- Police: Sometimes patrolling the cities on foot or by car, they will appear once the alertness level reaches the second stage. They are armed with either pistols (Colt 1911s) or shotguns. They take more damage than farmers and regular civilians, requiring two disintegrator shots, more Zap-O-Matic, or longer brain extraction time. Cortex scans reveal them to be corrupt cops who feel they are above the law and often taking bribes. They are not present in Area 42, where they are replaced by the Army.
- Army: Found patrolling by foot, like the police, in Area 42, Union Town, and Capitol City. They will also show up in trucks once alert level 3 is reached. They carry M1 Garand rifles. They are tougher than the Police, and require three shots from the Disintegrator Ray to kill. Cortex scans reveal these soldiers to be disgruntled with the Army, but they remain due to their rather disturbing desire to shoot someone. When incognito, some of the soldiers will try to bribe the alien with Reese's Pieces (which didn't exist until the 1980s), a reference to the movie E.T.
- Majestic: Shown once in the first mission and then showing up later in the game as a threat, the Majestic patrol Union Town and Capitol City, and will arrive at alertness level four. They carry either blaster pistols or more powerful disruptor rifles that resemble Furon technology. The strongest of the humans. They are described by Pox as "Men in...really, really, dark brown".
- Majestic Psi-Mutant: A Majestic agent with modified genes to access their dormant Furon DNA. However, they are much less intelligent than normal humans, as evidenced by their thoughts. An example is "One plus one equals...window. Hurr hurr hurr." They attack with force waves, can raise a defense shield, can send out waves draining Crypto of his mental reserves, and force Crypto to create a holobob. They have a very high DNA value if their brain is extracted. In most cases, the DNA is 150, but in some rare cases, it is as high as 300.
- Tanks: Typically seen at alertness level three with the Army. Tanks shoot at Crypto and at the saucer. They do little damage to the saucer, but one shot will nearly kill Crypto. The tank's splash damage can be used to the player's advantage.
- Gun Turrets: Small automated machine guns that shoot on sight.
- Anti-Aircraft Guns: They will lock onto Crypto on the ground, but will only fire at the saucer or if Crypto flies with the jetpack.
- Anti-Aircraft Missile Turrets: They will only shoot at the saucer. They fire target-seeking missiles which do fair damage.
- Powersuit Soldiers: Seen in Area 42, Union Town, and Capitol City, as well as briefly in Santa Modesta. Majestic collaborations with the military to create a large suit that looks robotic, but in fact has a human commander inside. Capable of shooting at Crypto or stomping the ground to release a shockwave. Powersuit Soldiers can see through Crypto's holobob. Although they look menacing, they can be easily destroyed by PK.
- EMP Mines: Majestic tools which emit an electromagnetic pulse when Crypto comes nears them, temporarily disabling his weapons and jetpack.
- Tesla coils: They will fire electricity bursts at the saucer, doing significant damage. They are best destroyed on foot as they can not fire at Crypto.
- Land Mines: In Area 42 & some other places, mines will be planted that will explode the minute anything touches them.
- Air Mines: In Area 42 & some other places, Hot Air Balloons will float around that will explode the minute anything touches them.
- Armquist: Armquist will pilot a giant exo-suit. More powerful than the basic robots, it will fire basic shots, a barrage of missiles that will rain down on Crypto, and can stomp the ground if Crypto is nearby, knocking him down.
- Roboprez: Essentially, the brain of President Huffman placed in a 50-foot-tall Mech. He fires homing missiles and a powerful energy blast from his chest.
- Silhouette: This final battle takes place at the Octagon. She is armed with a pair of Laser Pistols and has the enhanced Furon DNA in her genes which gives her the ability to shield temporarily and heal. She is also able to do flips and spins all around the battlefield and kicks when fought up close.