Photobiomodulation (PBM) therapy has been noted to promote cell proliferation and growth in many different cell types shown both in vitro and in vivo. Currently, treatment regimens are used in the clinic for a variety of ailments, including wound healing. However, most protocols treat an anatomical site without considering individual cell types constituting the target tissues. This study investigates the maximal dose threshold for oral keratinocyte and fibroblast cell types treated with near‐infrared laser therapy. We observed keratinocytes have increased sensitivity to laser irradiances (>0.047 W/cm2, 300 sec, 14.2 J/cm2) compared to the fibroblast cells (>0.057 W/cm2, 300 sec, 15.1 J/cm2) (p < 0.0001). Laser treatments were noted to generate increased reactive oxygen species (ROS) levels in keratinocytes compared to fibroblasts that appeared to inversely correlate with higher basal catalase expression. To validate these observations, melatonin was used to treat keratinocytes to induce catalase activity (p < 0.0001). Increased melatonin‐induced catalase levels were noted to significantly improve keratinocyte survival to phototoxic laser doses. These observations suggest that clinical laser dosing should account for differential effects of lasers on individual cell types to improve safety and clinical efficacy of PBM therapy. magnified image