Osteoporosis is a globally relevant public health issue. Our study aimed to summarize the knowledge on the proteomic biomarkers for low bone mineral density over the last years. We conducted a systematic review following the PRISMA guidelines; the scoured databases were PubMed, Web of Sciences, Scopus, and EBSCO, from inception to 2 June 2023. A total of 610 relevant studies were identified and 33 were assessed for eligibility. Finally, 29 studies met the criteria for this systematic review. The risk of bias was evaluated using the Joanna Briggs Institute Critical Appraisal Checklist tool. From the studies selected, 154 proteins were associated with changes of bone mineral density, from which only 10 were reported in at least two articles. The protein–protein network analysis indicated potential biomarkers involved in the skeletal system, immune system process, regulation of protein metabolic process, regulation of signaling, transport, cellular component assembly, cell differentiation, hemostasis, and extracellular matrix organization. Mass spectrometry-based proteomic profiling has allowed the discovery of new biomarkers with diagnostic potential. However, it is necessary to compare and validate the potential biomarkers in different populations to determine their association with bone metabolism and evaluate their translation to the clinical management of osteoporosis.