Botrytis cinerea is one of the most important postharvest pathogens and causes huge economic losses worldwide. Ambient pH is a critical factor influencing virulence of B. cinerea. In this study, BcpacC, a crucial gene encoding a pH-responsive transcription factor, was knocked out in B. cinerea strain B05.10. Deletion of BcpacC resulted in pH-dependent reduction in mycelial growth, sporulation, and virulence in apple and tomato fruit, and romaine lettuce leaves. An iTRAQ based proteomic analysis identified 70 differential proteins involved in various biological processes between wildtype (WT) and ΔBcpacC mutant under pH 6 condition, including 18 proteins related to secondary metabolism. Gene expression analysis indicates that 37 of all the 42 secondary metabolism key enzyme encoding genes were regulated by BcPacC. Further, three PacC-regulated polyketide synthase encoding genes, Bcpks4, Bcpks5 and Bcpks11, were knocked out and first proved to contribute to sporulation and virulence in B. cinerea. Our results revealed that the extensive regulation of BcPacC on secondary metabolism might play crucial roles in development and pathogenicity of B. cinerea during adaption to ambient pH.