Skin wound infections and sepsis caused by pathogenic bacteria that are resistant to multiple classes of antimicrobials account for massive morbidity and mortality in humans and emerging losses in animals worldwide. New drug classes are urgently needed to address the increase and global spread of antimicrobial resistance. However, animal models for detailed investigation of disease progression in a scenario that mimics bacterial infection in humans and animals often involve using separate animal cohorts at each stage of disease. We have developed and optimised bioluminescent (light-emitting) models of dermal partial-thickness scald wounds and sepsis in mice by infection with a recombinant luciferase-expressing Staphylococcus aureus strain (Xen29). For the skin scald wound model, mice were infected with 1.5 x 107 CFU of Xen29 two days post-wounding and then treated twice daily with either a 2% topical mupirocin ointment or PBS control, over 7 days. For the sepsis model, mice were infected with a lethal dose (2.5 x 107 CFU) of Xen29 intraperitoneally (IP). At 2 h and 6 h post-infection, mice were treated IP with 6 mg/kg daptomycin or vehicle and time to moribund monitored for 72 h. Consistent and reproducible bacterial burden data were obtained from individual mice on a Xenogen IVIS Lumina XRMS Series III live animal biophotonic imaging system, with concomitant significant reduction in photon intensities in drug-treated mice. Post-mortem histopathological wound examination and bacterial counts in blood correlated strongly with disease severity and Xen29 total flux. The bioluminescent models have great potential to replace laborious and costly microbiology techniques associated with colony counting of bacteria derived from infected mice. The model will also allow preclinical evaluation of the efficacy of new drug classes for treating acute and chronic bacterial infections in humans and animals, and holds promise for assessment of the population dynamics of multiple bacterial infections.