The rotator cuff is prone to injury, remarkably so for manual wheelchair users. To understand its pathomechanisms, finite element models incorporating three-dimensional activated muscles are needed to predict soft tissue strains during given tasks. This study aimed to develop such a model to understand pathomechanisms associated with wheelchair propulsion. We developed an active muscle model associating a passive fiber-reinforced isotropic matrix with an activation law linking calcium ion concentration to tissue tension. This model was first evaluated against known physiological muscle behavior; then used to activate the rotator cuff during a wheelchair propulsion cycle. Here, experimental kinematics and electromyography data was used to drive a shoulder finite element model. Finally, we evaluated the importance of muscle activation by comparing the results of activated and non-activated rotator cuff muscles during both propulsion and isometric contractions. Qualitatively, the muscle constitutive law reasonably reproduced the classical Hill model force-length curve and the behavior of a transversally loaded muscle. During wheelchair propulsion, the deformation and fiber stretch of the supraspinatus muscle-tendon unit pointed towards the possibility for this tendon to develop tendinosis due to the multiaxial loading imposed by the kinematics of propulsion. Finally, differences in local stretch and positions of the lines of action between activated and non-activated models were only observed at activation levels higher than 30%. Our novel finite element model with active muscles is a promising tool for understanding the pathomechanisms of the rotator cuff for various dynamic tasks, especially those with high muscle activation levels.