Exoskeletons have been gaining popularity for use in industrial applications and rehabilitative medicine. The arm-supporting exoskeleton (ASE) is one of the exoskeletons being utilized to reduce the shoulder muscle force required for individuals to perform overhead work. Many studies have been done showing efficacy in reducing the subjects’ anterior and medial deltoids' muscle activity. User characteristics like sex and anthropometrics effect on muscle activity has not been analyzed. The objective of this study was to determine if the specific arm supporting exoskeleton, anthropometric categorization, and sex level affect the subjects’ muscle activity and then determine if these characteristics interact with each other. To fulfill this objective, 26 subjects participated in overhead drilling simulations with EMG monitoring, using four different ASE (SuitX, Comau Mate, Eksovest, and Levitate Airframe) and once without. Significant differences were found between subjects categorized as small, medium, and large, with a medium effect size. The Eksovest ASE provided a significantly higher muscle activity reduction than the other exoskeletons. There was an interaction between exoskeletons and the size of subjects; the effect was larger when completing lower elevation tasks. Sex differences in muscle activity reduction may have been caused by bone structure or general sized differences. Overall, ASE are beneficial for overhead tasks, regardless of sex, and most subject sizes. The interactions between the variables are small enough to not be a concern when purchasing an arm-supporting exoskeleton.