This study used an OpenSim inverse-dynamics musculoskeletal model scaled to subject-specific anthropometrics to calculate three-dimensional intersegmental moments at the shoulder, elbow and wrist while 10 subjects used 1 and 2 lb hammers to drive nails. Motion data were collected via an optoelectronic system and the interaction of the hammer with nails was recorded with a force plate. The larger hammer caused substantial increases (50–150%) in moments, although increases differed by joint, anatomical component, and significance of the effect. Moment increases were greater in cocking and strike/follow-through phases as opposed to swinging and may indicate greater potential for injury. Compared to shoulder, absolute increases in peak moments were smaller for elbow and wrist, but there was a trend toward larger relative increases for distal joints. Shoulder rotation, elbow varus-valgus and pronation-supination, and wrist radial-ulnar deviation and rotation demonstrated large relative moment increases. Trial and phase durations were greater for the larger hammer. Changes in moments and timing indicate greater loads on musculoskeletal tissues for an extended period with the larger hammer. Additionally, greater variability in timing with the larger hammer, particularly for cocking phase, suggests differences in control of the motion. Increased relative moments for distal joints may be particularly important for understanding disorders of the elbow and wrist associated with hammer use.