Dysregulated adaptive remodeling of the hematopoietic system under high-altitude hypoxic conditions constitutes the core cause of high-altitude polycythemia (HAPC), and the classic hypoxia-inducible factor-erythropoietin axis theory fails to fully elucidate the mechanisms underlying its pathological transition. Recent studies have revealed that hypoxia drives the expansion of a multipotent progenitor subset with high expression of transcription factor FOS, shifts lineage differentiation toward erythroid cells and establishes hypoxic hematopoietic memory. At the same time, ferroptosis in splenic macrophages impairs erythrocyte clearance and upregulated CD47 enables red blood cells to evade phagocytosis, with all these processes collectively contributing to HAPC pathogenesis. Genetic and inflammatory factors exacerbate individual variability. Based on the above pathological mechanisms, mesenchymal stem cell therapy delivers therapeutic benefits by stabilizing the hematopoietic microenvironment, relieving inflammation and oxidative stress, repairing multi-organ injuries and improving systemic oxygen supply to target both pathogenic origins and secondary lesions, yet its clinical application is currently restricted by bottlenecks such as severe cellular heterogeneity and inadequate targeted homing capacity. Therefore, future work should combine susceptibility gene screening with optimized stem cell technologies to advance the prevention and treatment of HAPC from symptomatic intervention toward precise regulation at the source of lesions.