Objective Although commonly prescribed, exercise therapy alone is insufficient for the treatment of low back pain (LBP). Thus, studies recommend a combination of interventions. Photobiomodulation therapy (PBMT) involving low-level laser is an effective intervention for relieving LBP; however, scientific evidence on the effects of laser therapy combined with exercise therapy is scarce and contradictory. The aim of this clinical trial is to evaluate the short-term and long-term effects of the combination of PBMT and an exercise protocol in individuals with persistent nonspecific LBP. Methods This 2-armed, randomized, placebo-controlled trial with blinded participants, assessors, and therapists will be conducted in the outpatient physical therapy clinic of a university in Diamantina, Brazil. Participants are 90 individuals between 18 and 65 years of age with self-reported LBP. The participants will be randomly allocated to (1) a 6-week exercise program combined with active PBMT at a frequency of twice per week, totaling 12 sessions (n = 45), or (2) a 6-week exercise program combined with placebo PBMT (n = 45). Clinical outcomes will be measured at baseline as well as at 8 and 20 weeks and 12 months after randomization. The primary outcomes will be pain intensity and disability. The secondary outcomes will be mental health, mobility, disability, and strength of the trunk extensor muscles. Conclusions and Potential Impact The findings will help determine whether adding PBMT to a physical therapist–supervised exercise protocol is more effective than the exercise protocol alone for persistent LBP. This study has the potential to guide clinical practice toward innovative ways of providing health care.