Following the aging of the population, cognitive impairment is becoming a major public health issue. Research in recent years has highlighted the potential of docosahexaenoic acid (DHA), folic acid (FA), and phosphatidylserine (PS) to improve synaptic plasticity and reduce inflammatory response. However, whether a combined intervention is more effective than using these supplements alone remains unclear. To investigate this, we conducted an experiment on D-galactose-induced aging mice and found that the combining DHA, FA, and PS (DFP) improved spatial learning memory. Moreover, the DFP treatment restored cognitive performance by regulating antioxidant levels, inhibiting microglia activation, and reducing inflammation. The treatment also increased the expression of neurotrophic factors and synaptic-related proteins in the hippocampal region of the brain. Our findings suggest that the supplementation of DPF could be more beneficial than using DHA alone. This combined intervention could improve neurotrophic factor expression and decrease neuroinflammation in the brain of mice, thus reducing neuron damage and enhancing synaptic plasticity. In summary, our results indicate that the combined supplementation of DFP may improve cognition, and may be more effective than supplement with DHA alone.