"The third hit increases your damage done by 0.25. This effect can stack but stops after 30 sec or if you are dealt damage."
Synergies
The Hunter's Grenade can be used to artificially elite enemies if the player can still extract a blueprint from the enemy, which will enable the crit condition. Slaying the artificial elite will drop the previously used Hunter's Grenade, allowing for an endless cycle.
The mutation Tainted Flask can be used in conjunction with the Hunter's Grenade.
Secondary weapons, particularly specialized crowd control weapons such as Symmetrical Lance and War Spear can compensate for Giantkiller's low damage in biomes.
The mutation Counterattack can be used to compensate for the Giantkiller's low damage on non-elite and non-boss enemies.
Notes
To truly take advantage of Giantkiller's very high damage, the player needs to land the third and fourth hit of the attack combo, which puts them at risk of getting hit due to their slow wind-up. Therefore, using Giantkiller against normal enemies is even further disincentvised.
The Giantkiller cannot be stored in the backpack.
This is for balancing reasons to prevent the player from easily defeating bosses while still being able to wreak havoc on normal enemies.
This can be partially circumvented by dropping the Giantkiller and replacing it with the other desired weapon for the level before returning and equipping it while placing the other weapon in the backpack.
The Cursed Sword, by contrast, needs no such limitation since the core tradeoff of that weapon (very high damage and fast attack rate, at the cost of being cursed) isn't compromised by the backpack mechanic: the curse downside still applies even when the weapon is stored away.
Trivia
When this weapon was originally introduced, it was only available through the Daily Run. It was impossible to unlock the Giantkiller under normal gameplay and was thus only obtainable through modding.
The Giantkiller may have initially been conceived as a spear, like the one originally used to "kill" the Giant, but was changed to a sword at some point before being added to the game files.
The in-game model for the Giantkiller appears to be a sword with a long, straight-edged blade, with a white glow. This model is currently also used for the Seismic Strike and the Swift Sword.
The flavor text is a reference to the phrase "The bigger they are, the harder they fall".
3.5: Changed the Legendary Affix's effect from "Your last attack deals 2 times more critical damage" to "The third hit increases your damage done by 0.25. This effect can stack but stops after 30 sec or if you are dealt damage".