The effect of postharvest oxalic acid (OA) treatment on pink rot caused by Trichothecium roseum and its possible mechanisms of action in muskmelon (Cucumis melo L. cv. Yindi) fruit were investigated. Dosage of OA treatment at 25–100 mM was effective to reduce disease severity on fruit inoculated with T. roseum, with the greatest efficacy being achieved using 50 mM OA. Higher concentration (200 mM) failed to promote better control of the decay-causing agent and caused phytotoxicity. OA treatment at 50 mM increased the activities of peroxidase (POD), polyphenoloxidase (PPO), phenylalanine ammonia-lyase (PAL), β-1,3-glucanase (GLU), and superoxide dismutase (SOD), while inhibiting the reduction in the activity of catalase (CAT). OA treatment also promoted the accumulation of total phenolic, flavanoid, and lignin. Microscopic and ultrastructural observation revealed that histological structure as preventive barrier was markedly strengthened by OA. Furthermore, the above-mentioned enzymes activity, metabolites content, and histological structure were more profoundly enhanced or reinforced in OA-treated fruit after inoculation with T. roseum, compared to those with OA treatment alone. The results suggest that the priming of defense responses is involved in OA-induced disease resistance for more effective resistance in harvested muskmelon fruit.