Light signals and plant hormones are involved in regulating the growth, development and stress resistance of plants; however, it remains unclear whether light affects hormones and thus pathogen resistance in oriental melon. Here, we found that red light promoted salicylic acid (SA) accumulation and powdery mildew resistance by activating the transcription of CmICS, the key gene for SA biosynthesis, and silencing CmICS seriously weakened the induction effect of red light on powdery mildew resistance in oriental melon leaves. Further studies showed that red light induced the expression of CmWRKY42 under powdery mildew stress, and CmWRKY42 directly bound to the CmICS promoter to activate its expression and promote the accumulation of SA under red light. Furthermore, we found that PHYTOCHROME INTERACTING FACTOR 8 (PIF8), as a negative regulator of SA biosynthesis, inhibits CmWRKY42 transcriptional activation by binding to the CmWRKY42 promoter, and thus inhibits transcriptional activation of CmICS by CmWRKY42. Also, CmPIF8 binds to the CmICS promoter and directly inhibits its transcription. In conclusion, our study revealed a new molecular mechanism of the relationship between red light-SApowdery mildew resistance and provided a theoretical basis for resistance breeding of oriental melon.