The Python is a double-action revolver which fires one round. It is very powerful, but it has a long reload time and low rate of fire. It has near perfect accuracy, but rapidly firing shots will cause accuracy to significantly decrease because of the weapon's fair amount of recoil.
The Colt Python can kill anything weaker than a Bullsquid and Overwatch Soldier (in easy) in one shot. While this may sound tempting, it is better to conserve Colt Python ammo for foes that require multiple shots to take down, such as Alien Grunt, Alien Controller, Poison Zombie and Overwatch Elite. All of the enemies that can be killed with one Colt Python shot can also be killed with double HECU Shotgun blast or one Combine Shotgun blast (as provided all pellets hits the target), which has much more ammo scattered throughout the game than the Colt Python does.
In Half-Life multiplayer and Half-Life: Source, the secondary fire button triggers a zoom which may be used for long-range sniper shots.
Since it has no built-in scope in Half-Life 2, the HEV Suit zoom can be used to aim for long distance shots. The player should zoom into the target and have the desired target in the center of their crosshair, then the zoom must be quickly released and the player must fire. Alternatively, a player may hold down the primary fire button while the zoom is being released to instantly fire a round and diminish jolting.
Ammunition for this weapon is very rare in all of the games, so one should use this weapon only when its pinpoint accuracy and stopping power is required, such as against Alien Grunts, Overwatch Elites and Hunters standing far away.
Using this gun in the deathmatch modes can result in many easy kills at any range as long as one aims for the head.
Assuming ammunition is plentiful for other weapons, the Colt is good to use against Poison Headcrabs, as it will kill them in one hit at any range.
This is the most effective firearm against Hunters. The source code states that this is because players perceive the weapon as the strongest in the game.
As heard in the Half-Life sound file get_44pistol.wav and as seen on the cut ammo box model, the Half-Life Python was originally to be a .44 Magnum revolver.
The Half-Life Deathmatch Python model features an attachment under the barrel that resembles a laser pointer but acts as a scope and emits a fake laser (as a small red dot in the center of the screen). While that scope is not present in Half-Life Deathmatch: Source or Half-Life: Source, its function remains. This attachment was originally to appear in Half-Life's singleplayer mode as well.
In the Half-Life 2 series, all six bullets of the Python's cylinder are reloaded together, but there is no speedloader (the bullets just float in mid-air as a circular group). The animation is instead more suited for the application of a moon clip. Overall this is merely a design oversight.