- "Made of low-grade Kryptonite. Radioactive mineral from your home planet. It weakens you."
- —Hank Henshaw[src]
Kryptonite is normally green and Kryptonians exposed to the element will become weak within close proximity or pierced by weapons laced or made from the substance, and prolonged exposure to the element for Kryptonians is fatal. Kryptonite's effects is radioactive in nature and therefore cannot penetrate the element lead. The radiation of the mineral can be harnessed and used independent of the mineral itself to harm a Kryptonian, usually appearing in the form of artificial light emitted from certain machinery. Alex taught Kara to fight in a room lined with low-intensity Kryptonite emitters, just enough to be brought down to normal strength. Alex Danvers utilized a sword made from Kryptonite, and it was ultimately used to kill Astra. Physical signs of being affected by Kryptonite are somewhat fever-like, including nausea, weakness, dizziness, vertigo, fatigue, pain, and loss (or near loss) of consciousness. Physical contact with Kryptonite of higher intensity is enough to cause burning pain. It has even been used as anesthesia or a sedative against Kryptonians due to its affects. Kryptonite inside the body causes green glowing veins to protrude from the skin of the Kryptonian and the physical pain it causes becomes unbearable at that point.
The blue, molecular opposite of green kryptonite and was created by the D.E.O. by reversing the ionic charge of green kryptonite. It was used to subdue Bizarro. While it had no effect on Kryptonians, it severely weakened Bizarro and sedated her, allowing her to be captured and then put in a coma. It also seemed to have a calming effect on her, removing her rage toward Supergirl, causing her to accept the need to put her in a coma and ask for forgiveness for her actions. Therefore, it effectively made her more rational and understanding towards others, something she struggled with before.
Maxwell Lord created a synthetic red form in hopes of subduing Non's next attack. Rather than weaken a Kryptonian physically, Red Kryptonite alters his or her mind by weakening and gradually destroying their inhibitions, as well as bringing out every negative thought to the surface. They can even feel its effects long after they have left its presence. As this happens, red, glowing veins momentarily protrude from the skin when they first come near it and in times when the victim's actions and thoughts are most affected by the Red Kryptonite. Symptoms of Red Kryptonite infection first start as the Kryptonian becoming more abrasive and immature in personality and actions as their mental and emotional restraint is lessened. Eventually, the Kryptonian will be left without morality, patience, rationality or any cares, whatsoever. They can even develop narcissistic tendencies and arrogance that results in an inferiority complex. After having expressed their negative personality traits fully, the Kryptonian will become malevolent and prone to hostility and aggression, leaving them a danger to everyone around them. However, Maxwell also developed a cure for it in the form of a red energy beam gun that neutralized the Red Kryptonite at a targeted victim and knocked them out, as the Red Kryptonite left the body in the form of red gas.
- D.E.O.: Kryptonite is used by the members of the D.E.O., who utilize it against those that hail from the planet Krypton. They utilize it in the form of restraints and certain weapons, such as blades, darts and bullets. Prison cells designed for Kryptonians, as well as training rooms, have kryptonite lights that can be lowered to simply depower a Kryptonian, while higher levels can incapacitate, cripple, and nearly kill them.
- Maxwell Lord: He created Red Kryptonite in hopes of stopping Non's army. Unfortunately, Kara inadvertently came in contact with it. The Red Kryptonite lowered and gradually destroyed her inhibitions and turned her into a corrupt version of herself.
- Project Cadmus