The purpose of this study was to evaluate effects of hyperbaric oxygen (HBO) and penicillin (PCN) therapy in a murine model of streptococcal myositis. The thighs of Swiss Webster mice were inoculated with Streptococcus pyogenes. Four groups were evaluated: (1) control (N = 10), (2) HBO treatment (N = 10), (3) PCN treatment (N = 8), and (4) PCN and HBO treatment (N = 6). Mortality (day of death) and the number of colony-forming units (cfu) were measured. PCN significantly lowered cfu from control (p < 0.05). Cfu in group 4 was significantly lower than PCN alone (p = 0.006). Survival was significantly longer in the PCN group compared with the control (p < 0.01). Survival in the combined treatment group was significantly longer than PCN alone (p < 0.01). These results suggest that (1) HBO treatment alone does not decrease mortality or bacterial proliferation in vivo significantly, (2) PCN therapy alone improves outcome significantly, and (3) the combined treatment of PCN and HBO exerts at least additive effects in both decreasing bacterial counts in vivo and increasing survival in this model.