The regenerative potential of mesenchymal stem cell (MSC) secretomes in peripheral nerve injuries warrants rigorous evaluation. This systematic review analyzes their effectiveness in preclinical models of neurotmesis, a complete transection of a nerve. Neurophysiological recovery was assessed through nerve conduction velocity (NCV), a measure of the speed at which electrical impulses travel along a nerve. Following PRISMA guidelines, a systematic search was conducted in PubMed, Scopus, Web of Science, and ScienceDirect (last search July 2024). From 640 initially identified studies, 13 met inclusion criteria, encompassing 514 animals (rats). experimental designs published since 2014 in English or Spanish, focusing on MSC secretomes for nerve regeneration. Exclusion criteria included reviews, case reports, and incomplete data. The risk of bias was assessed using Joanna Briggs Institute tools. Results were synthesized narratively, focusing on functional and structural outcomes. The included studies employed various MSC sources, including adipose tissue, olfactory mucosa, and umbilical cord. Nine studies reported enhanced SFI, favoring secretome-treated groups over controls (mean difference +20.5%, p < 0.01). Seven studies documented increased NCV, with up to 35% higher conduction velocities in treated groups (p < 0.05). Histological outcomes reported in 12 studies showed increased axonal diameter (+25%, p < 0.01), myelin sheath thickness (+30%, p < 0.05), and Schwann cell proliferation. Limitations of the included evidence include methodological heterogeneity and variability in outcome measurement tools. MSC-derived secretomes demonstrate potential as advanced therapeutic strategies for nerve injuries. Personalized approaches considering injury type and clinical context are essential for optimizing outcomes.