Blue mold is one of the most serious postharvest diseases in apples caused by Penicillium expansum. The purpose of this study is to determine the effect of epsilon-poly-L-lysine (epsilon-PL) on the pathogenicity of P. expansum and explore the potential mechanism from the perspective of organic acid. The study investigates the effect of E-PL treatment on the growth and acid production of P. expansum in vitro and in vivo. When the concentration of epsilon-PL was 50 mg/L, the growth of P. expansum was inhibited and the decrease in pH value was delayed in the medium. For example, on the third day of culture, P. expansum reduced the pH of the medium from 6.1 to 4.15, and epsilon-PL inhibited the decrease in the pH value at most 34.4%. When the concentration reached 1000 or 2000 mg/L, the infection of P. expansum in fruits was effectively inhibited. During the growth and infection of P. expansum, gluconic acid is one of the main factors leading to the pH value falling in the local environment. After epsilon-PL treatment, the accumulation of gluconic acid decreased, the activity of glucose oxidase was suppressed, and then the decline in the local environmental pH slowed down. In addition, after epsilon-PL treatment, the activities of cell-wall-degrading enzymes, such as cellulase (CL) and polygalacturonase (PG), in the different areas of the P. expansum-apple interaction were also affected by pH change. The results show that epsilon-PL inhibited the pathogenicity of P. expansum by affecting the accumulation of gluconic acid and slowing the decline in pH in fruit tissues, so as to affect the pathogenicity of P. expansum. This is the first time that the mechanism of epsilon-PL interfering with the pathogenicity of P. expansum from the perspective of organic acids is clarified.