Post-stroke depression (PSD) constitutes a significant complication that influences both patient survival and functional recovery following a stroke. Despite its prevalence, PSD still lacks a long-term, safe and effective treatment measure. Remote ischemic conditioning (RIC) is a simple and noninvasive procedure that exert neuroprotective effects. This pilot study aims to investigate the efficacy, safety, and feasibility of RIC as a preventive measure against PSD.Acute ischemic stroke patients within 15 days post-event were considered eligible for study enrollment. Fifty participants were recruited and underwent daily RIC treatments for a 12-month period. Depressive symptoms were assessed utilizing the Patient Health Questionnaire-9 (PHQ-9) and the Hamilton Depression Rating Scale (HAMD) at baseline, as well as at 1, 3, 6, and 12-months post-intervention.The study found a gradual improvement in depressive symptoms among the 50 patients who completed the study over the 12-month treatment period, as evidenced by a consistent decline in pertinent scores. Moreover, merely two patients experienced mild adverse reactions.The study's outcomes indicate that RIC is safe, well-tolerated, and feasible as a preventive measure for PSD. Consequently, it is advisable to conduct a comprehensive randomized controlled trial to further evaluate the effectiveness and safety of RIC in preventing PSD.© 2025 Li et al.