INTRODUCTION: Deep Brain Stimulation (DBS) and Spinal Cord Stimulation (SCS) represent burgeoning treatments for diverse neurological disorders. This systematic review aims to consolidate findings on the immunological and endocrine effects of DBS and SCS, shedding light on the intricate mechanisms of neuromodulation. MATERIALS AND METHODS: This systematic review, aligned with PRISMA protocols, synthesizes findings from 33 references-20 on DBS and 13 on SCS-to unravel the immunological and endocrine impacts of neuromodulation. RESULTS: DBS interventions exhibited divergent effects on cytokines, with an increase in hepcidin levels and a variable impact on the IL-6/IL-10 ratio. While some studies reported elevated IL-6, animal studies consistently demonstrated a reduction in IL-1β and IL-6, with no significant changes in TNF-α and an increase in IL-10. Noteworthy hormonal changes included decreased corticosterone and ACTH concentrations and increased oxytocin levels following DBS of the hypothalamus. SCS mirrored similar effects on interleukins, indicating a reduction in IL-6 and IL-1β and an increase in IL-10 levels. Additionally, SCS led to reduced VEGF levels and elevated expression of neurotrophic factors such as BDNF and GDNF, particularly under burst stimulation. CONCLUSIONS: Both DBS and SCS exert anti-inflammatory effects, manifesting as a decrease in pro-inflammatory cytokines alongside the stimulation of anti-inflammatory cytokine synthesis. These findings, observed in both animal and human models, imply that neurostimulation may modify the trajectory of neurological diseases by modulating local immune responses in an immunomodulatory and endocrine manner. This comprehensive exploration sets the stage for future research endeavors in this evolving domain.