In the entire trilogy, as well as Halo 4, the Plasma Pistol is most effective in close-quarters when facing Elites, Brutes, or Knights, by first depleting their shield and then switching to a headshot-capable weapon. In Halo 3: ODST, this will grant the player the My Clothes! achievement. Eliminating an enemy with this tactic will award the player an EMP Kill Medal in both Halo 3 and Halo 3: ODST.
Going up against Elites in Halo: Combat Evolved, an effective up-close-and-personal strategy is to fire as fast as you can pull the trigger-- the shots will stun the Elite long enough for you to get up and melee him.
In "Two Betrayals" the moment you begin switch to the Plasma Pistol and dodge behind the glass, charge up the Plasma Pistol and aim slightly ahead of where the Sentinel is heading, if timed just right you will take down all of them and still have enough ammo left to tackle the Elites in the Control Room's hallway.
In Halo: Combat Evolved, the Plasma Pistol's semi-auto mode is as powerful as the Plasma Rifle and Assault Rifle when used against shields. However it does slightly less damage against flesh. Because it also has the overcharge feature, it's a good idea to drop those two weapons for the PP in most cases. This is, however, not an advisable tip in Halo 3because of the increased power of the latter two weapons, and the drain on a Plasma Pistol's battery when overcharged.
In Halo: CE Multiplayer, the same strategy used against Elites also applies to your opponent in Multiplayer. Fire as fast as you can until you get in melee range.
Using an overcharge can be effective against vehicles particularly if they are jumping or out of control, or headed your direction. This is a useful skill in Halo 3 as an overcharged shot can disable vehicles.
The Plasma Pistol is quite useful for taking out Campers in maps such as Rat Race, where there are Covenant Shields, because it is capable of disabling shields temporarily, opening up the camper to shots from your team mates or use your secondary weapon if you are doing this alone.
The Plasma Pistol has been synonymous for the Halo 2-coined term "Noob Combo". By equipping the Plasma Pistol with a headshot-capable weapon, using the Plasma Pistol to drain the enemy's shield and then finishing him off with the headshot-capable weapon can take out an opponent in seconds. It is most effective in Halo 2, though overpowered and overused. In Halo 3 it can still be accomplished, if at close range or close-quarters.
In Halo 3, the Plasma Pistol is the best weapon to use when disabling vehicles when a Power Drain is not available, followed by a Plasma Grenade stick. However, impacting an overcharge with fast-moving vehicles will require a great deal of luck, timing and skill. A direct Plasma Grenade stick will be a better alternative. The Banshee will prove the most difficult because of its speed. The best tactic is to hide behind cover, luring the Banshee until it either attempts to splatter you or bomb you. However, note that Banshee pilots would be extra careful when they notice a green glow emitting from your weapon.
Another common tactic is to use a charged shot to the head and follow it up with a melee attack.
When on a team, have one player fire an overcharge at your enemy then have another finish them off when their shields are depleted and they're at their most vulnerable.