Four months after the events of the Lost Water Medallion, Cyrus finds himself facing internal conflict for leaving his highland home and departs Zora's Domain and his wife without warning. Ruto miraculously finds him once again, and discovers that something dark festers in the old Castle Town across the desert and that only the combined might of zoras and highlanders can stop it.

The Lost Water Medallion chronicles the adventure of Cyrus the mercenary from the Trilby Highlands to retrieve the Water Medallion, which has been missing since the events that took place in Twilight Princess, namely the death of the Sage of Water. Cyrus is joined in his quest by Murad, the cowardly descendent of the Hero of Time, and by Ruto XVI, Princess of the Zora tribe.