Mycobacterium ulcerans (M. ulcerans) causes Buruli ulcer, a very debilitating disease that affects the skin and other tissues. The disease occurs mainly in children in sub-Sahara Africa. While contracture, fibrosis and functional limitation of range of motion are frequent complications of Buruli ulcer, no fundamental or clinical studies have investigated the impact of M. ulcerans infections on skeletal muscle. In the present study, we subcutaneously infected mice in the proximity of the right biceps muscle to evaluate the histological, biochemical and functional impact of M. ulcerans on skeletal muscles. The concentration of mast cells decreased but the number of neutrophils and macrophages increased steadily in proximate-infected biceps muscles. Pro- and anti-inflammatory cytokines as well as fibrogenic growth factor mRNA also increased. Significantly more membrane damage and fibrosis occurred in proximate-infected biceps muscles than in control and sham muscles. Passive biomechanical testing also revealed that the presence of M. ulcerans increased muscle stiffness. These findings show for the first time that M. ulcerans can induce local and chronic inflammatory responses in skeletal muscles that are associated with muscle fiber damage and fibrosis.