We report the case of a 3-week-old infant referred for evaluation of sudden onset jaundice and unexplained hemolysis. After an exhaustive workup, the most likely etiology was found to be envenomation by a brown recluse spider, Loxosceles reclusa. This case underscores the fact that severe loxoscelism may occur in the absence of the classically described necrotic cutaneous lesion, and represents one of the youngest presumed cases of loxoscelism. We present the case to illustrate the importance of considering loxoscelism in the differential diagnosis of sudden massive hemolysis in children, particularly in endemic areas of the midwestern and southern United States.