Accumulating evidence has shown that microRNAs (miRNAs) are involved in the pathophysiology of psoriasis. The present study aimed to identify the effect and mechanism of miR-138-5p in psoriasis. In the present study, we observed that miR-138-5p expressed higher levels in psoriasis tissues compared to the control. Results from biological software and dual-luciferase reporter assay illustrated that miR-138-5p directly targeted sirtuin 1 (SIRT1). Moreover, we observed that SIRT1 was down-regulated in psoriasis tissues. Therefore, we supposed that miR-138-5p and SIRT1 might regulate the progress of psoriasis. Additionally, the functions of miR-138-5p and SIRT1 on cell viability, cell apoptosis, inflammatory cytokines expression as well as signaling pathways were evaluated. The findings demonstrated that down-regulation of miR-138-5p significantly suppressed cell viability and promoted cell apoptosis accompanied with the decreased expression of Bcl-2 and increased expression of Bax. However, these effects were reversed by SIRT1-siRNA. It was also revealed that the mRNA expression levels of inflammatory cytokines including TNF-α, IFN-γ, and IL-22 were suppressed by miR-138-5p down-regulation in HaCaT cells, while the effects were overturned by SIRT1-siRNA co-transfection. Eventually, we found that miR-138-5p inhibitor suppressed the expression of p-p65 in NF-kB pathway at protein level, and the result was reversed by SIRT1-siRNA in a similar way. In general, our results elucidated that miR-138-5p played a crucial part in psoriasis progress through regulating the growth of keratinocytes and inflammatory responses by targeting SIRT1. Therefore, miR-138-5p might be considered as a novel target for the therapeutic strategies in psoriasis.