•ASA reduced fusarium rot severity and NEO distribution in muskmelon fruits inoculated with F. sulphureum.•ASA increased the generation of O2.− and H2O2 by activating plant membrane NOX.•ASA enhanced antioxidant enzymes’ activity of POD, CAT and SOD and ascorbate-glutathione cycle.•ASA improved gene expressions involved in ROS metabolism. Major losses in the harvested muskmelon fruit can be attributed to decay fungi. Fusarium sulphureum is the major causal agent of fusarium rot in muskmelon, which in turn, not only causes quality deterioration but also leads to neosolaniol (NEO) contamination. Therefore, new strategies to manage muskmelon postharvest decay and decrease NEO production are of paramount importance. Acetylsalicylic acid (ASA), a derivative of salicylic acid (SA), is a putative endogenous signal molecular and can induce resistance against decay fungi in postharvest fruit and vegetable. To investigate the mechanism of induced resistance by ASA treatment against fusarium rot of muskmelon, the fruit was treated with ASA, followed by the inoculation with F. sulphureum. Results showed that the reduction of fusarium rot severity and the suppression of NEO accumulation were linked with the elevation of ROS metabolism. ASA treatment enhanced ROS accumulation and induced the enzymatic activities and up-regulated gene expressions involved in ROS metabolism. Taken together, the present study provides substantial evidence which ASA induced resistance against F. sulphureum in muskmelon fruit to control the fusarium rot development.