Much like other pieces of Kryptonite, White Kryptonite was formed when the planet Krypton exploded. Similar to Red Kryptonite, White Kryptonite was Green Kryptonite until it passed through a band of space radiation that changed it. In the case of White Kryptonite, it became lethal to plant life and microorganisms, such as viruses and bacteria.

Superman first encountered as Superboy, when a descendant of Lana Lang that drew him into the 50th Century, where, due to loss of records from the 20th Century, he was viewed as a mythological character, similar to Peter Pan or Mercury. When a Creeping Blight spore from space arrives on Earth and begins growing "like a tidal wave", Superboy finds and uses White Kryptonite to destroy it after noticing that the Kryptonite destroyed the carnation he was wearing. In addition, Kryptonese on the White Kryptonite helped him prove to people in the 50th Century that Krypton existed, and thus he did as well.

White Kryptonite was first seen in the modern era in Superman's adulthood. When Perry White unknowingly became host for a parasitic, plant based alien named Xasnu. In a climactic fight in the Fortress of Solitude, Superman and Perry fought till all of Superman's defenses were destroyed. Before Perry could harm Superman further, though, Supergirl rushes in with a White Kryptonite meteor, destroying Xasnu.

When Superman became infected by the fatal Virus X, the Kryptonian Super Leprosy, he arranged for his funeral to consist of being launched into the brightest star in the known universe so his body would be disinfected after death. En route to the star, he passed by Htrae, the Bizarro World. The Bizarros, in their form of anguish, through chunks of Red and White Kryptonite at Superman's funeral ship. The White Kryptonite destroyed the Virus X, and Superman survived.

Superman later kept pieces of White Kryptonite, as well as a White Kryptonite ray, to help disinfect guests at the Fortress who were infected with something. The ray, in particular, was used to cure Supergirl when infected with Virus X.