Human Placenta-Derived Mesenchymal Stem Cells (HP-MSCs) are recognized for their potential in treating various diseases due to their multidirectional differentiation and immunomodulatory abilities. However, the therapeutic efficacy is often compromised in ischemic and hypoxic environments. Tremella Fuciformis Polysaccharide (TFP), a natural polysaccharide known for its immunomodulatory and anti-inflammatory properties, stands a good chance of overcoming this limitation. Our study investigates whether TFP enhances the therapeutic efficacy of HP-MSCs under ischemic-hypoxic conditions by inhibiting autophagy, with a focus on the role of the ERK signaling pathway. HP-MSCs were cultured under hypoxic conditions to simulate an ischemic environment and TFP was added to investigate its effects on MSC bioactivity, apoptosis, and proliferation. Mechanistic studies were conducted to assess the activation of the ERK signaling pathway and the expression of autophagy-related markers. TFP enhanced HP-MSC bioactivity under hypoxia by reducing apoptosis and promoting proliferation. Mechanistic analysis revealed that TFP enhanced the ability of HP-MSCs to adapt to hypoxic stress by activating the ERK signaling pathway. This activation led to the inhibition of autophagy-related markers, suggesting that TFP plays a protective role in hypoxia-induced cell stress. TFP enhances the therapeutic potential of HP-MSCs in ischemic-hypoxic conditions by inhibiting autophagy through ERK signaling pathway activation. These findings provide a theoretical foundation for the use of TFP in treating lower limb ischemia and highlight its potential to improve treatment protocols and outcomes.