In Call of Duty 4: Modern Warfare's multiplayer mode, all assault rifles except for the MP44 and AK-47 can be outfitted with a M203 Grenade Launcher. The AK-47 uses the GP-25 Grenade Launcher, and the MP44 cannot equip attachments. Interestingly, the G3, though compatible with the M203 PI variant, is only compatible with the normal M203 through modifications, and the G36C is not compatible with it at all. The M14, a weapon incompatible with the M203 in the basic form in which Call of Duty 4 presents it, would need incredible rail grafting to accommodate it, and even then, the bulky form of the weapon would not accommodate it well. The M203 variant mounted on the M4 Carbine and the M16A4 also differ from each other, with the M203 mounted on the M4 being an M203A1/M203 QA, which is designed to mount on a RAS bracket. Meanwhile, the ones on the M16 are standard M203, which only differs than the M203A1 by barrel lengths; the A1 uses 9" barrel, while the standard M203 uses 12" barrel. The grenades it shoots are slightly weaker than frag grenades, but they are also extremely accurate, fast-moving, and have very little arc. Also, it does not need to be unlocked through challenges. For these reasons it is generally looked down upon as unfair by many players when used in multiplayer, and is often referred to as the "noob tube". Many servers on the PC version either ban this attachment , or ban those using it. This attachment replaces Perk 1 in multiplayer. Even though leaf sights are present on both the M4 and the M16 when the M203 is attached they are never used. Most likely this is to not unbalance the accuracy between M203s with iron sights and M203s without.

The M203 shell will not detonate unless it has traveled a certain distance before hitting a surface. Thus, shooting at nearby walls, ground or ceiling will simply cause the shell to bounce harmlessly away. This makes using the M203 at close ranges very difficult. However, the shell will kill if it directly hits another player and has a special kill icon for kills achieved this way.

If the Overkill perk is used and both selected weapons have the M203 (or the GP-25) grenade launcher, then the player will have 4 40mm grenades (1 in each launcher and 2 spare ones for reloads). Since the M203 is a weapon attachment, players cannot pick up more ammo for it by walking over a dropped gun with a grenade launcher attached (unless they currently have the empty attachment up while doing so, prompting a reload). It can be difficult to gain more ammo for the M203 without respawning.

This attachment is mostly the same except now it does not take up a perk 1 slot. This means it can be used with perks like Bling, unlike Call of Duty 4. Sleight of Hand affects the reload speed effectively increasing its rate of fire. With the introduction of the Scavenger or One Man Army perk, one can technically acquire infinite numbers of grenades, however the player must switch to the launcher to pick up more ammo for it even if it's empty.

Getting 20 kills with an M203 attached to a specific assault rifle unlocks the Masterkey Shotgun for that weapon. Also, when picking up a weapon with this attachment, any unspent grenades will be added to the users inventory.

Due to the grenade launcher being frowned upon by many players, Treyarch has taken many steps to balance it: it costs 3000 CoD Points, cannot be used with the perk Warlord, its grenades are not replenished by the Scavenger perk, there are no explosive damage increasing perks like Danger Close, Fireworks, or Sonic Boom, and the perk Flak Jacket returns. It also cannot be used for the first 5 seconds of the start of a round. Also a grenade launcher can be attached to an AK74u.