The HK21 will kill in 3 shots at any range, or 2 headshots, and has medium recoil. This makes the HK21 extremely powerful at medium range. Long-range encounters can be dealt with by firing single shots. The HK21 is tied with the Stoner63 for the smallest capacity out of all the LMGs so the round drum attachment is extremely useful, as it doubles the ammunition capacity to 60 rounds. The iron sights, while clear and open, can be difficult to use. For this reason, the Red Dot sight or Reflex Sight is recommended.

The HK21 has a very slow movement speed, so users will benefit greatly from Lightweight. Steady Aim benefits the HK21 greatly as it drastically improves its CQB capabilities. Sleight of Hand is also very useful for this weapon, as it dramatically reduces the amount of time needed to reload, as well as increasing ADS speed with the Pro version.

The HK21 can be found in the Zombies game mode and is only obtained from the mystery box. It starts with a magazine size of 125 rounds and with a extra 500 rounds, therefore making it and the RPK the replacements for the MG42 and Browning M1919 in the Black Ops Zombies mode. When Pack-A-Punched, it becomes the 'H115 Oscillator'. This adds twenty-five rounds to the magazine while increasing ammo capacity along with the usual additions. The H115 Oscillator may also be a reference to Element 115.

The low rate of fire, very high magazine size and high reserve capacity makes ammo less of an issue for the HK21 than for other weapons. However, the very slow reload time makes Speed Cola useful when using this weapon. The low rate of fire also makes Double Tap Root Beer beneficial, but not a necessity. However, it may be wise to switch to a weapon with more mobility if fleeing becomes necessary, as the HK21 slows movement speed significantly.