Gray mold caused by Botrytis cinerea is one of the most prevailing deteriorative postharvest diseases in fruit and vegetables. Autophagy, a highly conserved mechanism in eukaryotes, is involved in defense responses against stresses, especially for pathogens infection in plants. However, limited studies have been conducted to elucidate the roles and regulatory mechanisms of autophagy in postharvest fruit disease resistance. In this regard, our earlier experimentation indicated that 50 mmol L⁻¹ lithium chloride (LiCl) and 5 mmol L⁻¹ hydroxychloroquine (HCQ) could be an autophagy activator and an autophagy inhibitor, respectively, that can reveal the role of autophagy in postharvest fruit defense against B. cinerea. Present findings further elaborated that the LiCl-mediated increase in autophagy activity showed concomitant higher expression levels of autophagy-related genes and the number of autophagosomes, whereas HCQ treatment reversed the phenomenon. LiCl-activated autophagy inhibited the disease as evidenced by lower disease incidence and lesion diameter, whereas HCQ application largely reversed this phenomenon. Transcriptome analysis revealed that the differentially expressed genes between LiCl-treated and control fruit were involved in the secondary metabolic pathway, represented by phenylpropanoid biosynthesis and reactive oxygen species (ROS) metabolism. LiCl treatment promoted the accumulation of total phenolics by activating phenylpropanoid biosynthesis. LiCl treatment also balanced ROS homeostasis by increasing antioxidant enzyme activities and regulating the ascorbate–glutathione cycle. Moreover, differentially expressed transcription factors between LiCl-treated and control fruit, such as WRKYs, MYBs, AP2, bHLH, HB-other, and MYB-related families might specifically affect the transcription of genes involved in ROS metabolism and phenylpropanoid biosynthesis. Meanwhile, MYBs (Solyc05g009230.1), bHLH (Solyc01g090790.2), and MYB-related (Solyc11g010710.1) transcription factors also participated in autophagy by directly binding to SlATGs (Solyc08g078820.3 and Solyc01g068060.3). These findings suggest that LiCl-induced autophagy results in increased activities of defense enzymes, activation of phenylpropanoid biosynthesis, and balance of ROS homeostasis, which contributes to disease resistance in postharvest fruit.