We examined a laser system (870 and 930 nm), employing wavelengths that have exhibited cellular photodamage properties in optical traps. In vitro, with 1.5 cm diameter flat-top projections (power density of 5.66 W cm−2), at physiologic temperatures, we achieved photoinactivation of Staphylococcus aureus, Escherichia coli, Candida albicans and Trichophyton rubrum. Using nonlethal dosimetry, we measured a decrease in trans-membrane potentials (ΔΨmt and ΔΨp) and an increase in reactive oxygen species (ROS) generation in methicillin-resistant S. aureus (MRSA), C. albicans and human embryonic kidney cells. We postulate that these multiplexed wavelengths cause an optically mediated mechano-transduction of cellular redox pathways, decreasing ΔΨ and increasing ROS. The cellular energetics of prokaryotic and fungal pathogens, along with mammalian cells, are affected in a similar manner when treated with these multiplexed wavelengths at the power densities employed. Following live porcine thermal tolerance skin experiments, we then performed human pilot studies, examining photodamage to MRSA in the nose and fungi in onychomycosis. No observable damage to the nares or the nail matrix was observed, yet photodamage to the pathogens was achieved at physiologic temperatures. The selective aspect of this near-infrared photodamage presents the possibility for its future utilization in human cutaneous antimicrobial therapy.