Photobiomodulation (PBM) encompasses a light application aimed to increase healing process, tissue regeneration, and reducing inflammation and pain. PBM is specifically aimed to modify the expression of cellular molecules; however, PBM impacts on cellular and molecular pathways especially in bone regenerative medicine have been investigated in scattered different studies. The purpose of the current study is to systematically review evidence on molecular impact of PBM on bone regeneration. A comprehensive electronic search in Medline, Scopus, EMBASE, EBSCO, Cochrane library, web of science, and google scholar was conducted from January 1975 to October 2018 limited to English language publications on administrations of photobiomodulation for bone regeneration which evaluated biological factors. In addition, hand search of selected journals was done to retrieve all articles. This systematic review was performed based on PRISMA guideline. Among these studies, five articles reported in vitro results, twelve articles were in vivo, and three of them were clinical trials. The data tabulated according to the type of markers (osteogenic markers, angiogenic markers, growth factors, and inflammation mediators). PBM's effects depend on many parameters which energy density is more important than the others. PBM can significantly enhance expression of osteocalcin, collagen, RUNX-2, vascular endothelial growth factor, bone morphogenic proteins, and COX-2. Although since the heterogeneity of the studies and their limitations, an evidence-based decision for definite therapeutic application of PBM is still unattainable, the findings of our review can help other researchers to ameliorate their study design and elect more efficient approach for their investigation.