Psoriasis is a common inflammatory dermatology disease. Strongly expressed serum amyloid A (SAA) promotes psoriasis exacerbation through inducing IL-17 secretion. What's more, SAA can stimulate the release of cathepsin B. The current work was performed to demonstrate the specific effects of cathepsin B silencing on inflammatory response, proliferation, and differentiation of IL-17A and SAA-induced keratinocytes and to report the precise role of cathepsin B in psoriasis-like lesion. HaCaT keratinocytes received treatment with IL-17A (0, 10, 50, 100 ng/ml) or SAA (0, 1, 5, 10, 20 μg/ml) for 24 h to establish psoriasis-like keratinocytes model. HaCaT keratinocytes were transfected with small interfering RNA (siRNA)-cathepsin B for the functional experiments. Cathepsin B mRNA and protein levels were separately assessed by performing RT-qPCR and Western blot analysis. Then, CCK-8 for detection of cell proliferative capacity and Western blot assay for detection of Ki67 and PCNA expression were adopted to evaluate the influence of silenced cathepsin B on proliferation of IL-17A/SAA-induced HaCaT keratinocytes. Furthermore, IL-6, IL-1β, TNF-α, and p-NF-κB p65 were detected to assess the effects of cathepsin B knockdown on inflammatory response in IL-17A/SAA-induced HaCaT keratinocytes. In addition, assessment of KRT10, FLG, and LOR levels were applied to analyze the function of cathepsin B silencing on differentiation of IL-17A/SAA-induced HaCaT keratinocytes. Cathepsin B expression is distinctly elevated in IL-17A/SAA-induced HaCaT keratinocytes. IL-17A or SAA treatment enhanced proliferation, promoted the release of inflammatory factors, and arrested differentiation in HaCaT keratinocytes. Furthermore, downregulation of cathepsin B reduced proliferation, suppressed inflammatory response, and boosted differentiation in IL-17A/SAA-induced HaCaT keratinocytes. To sum up, cathepsin B silencing rescued excessive proliferation and inflammatory response and scarce differentiation in HaCaT keratinocytes induced by IL-17A and SAA. These findings prompted that cathepsin B might be a promising therapeutic target for psoriasis-like lesion, which helps to develop an anti-psoriatic agent.