High levels of cell-free DNA (cfDNA) induce psoriasis. Currently, the treatment of psoriasis has the disadvantages of penetration difficulty, suppression of normal immunity, and skin irritation. In this study, biguanide chitosan microneedles (BGC-MNs) were prepared to treat psoriasis by removing cfDNA from the dermis through the skin barrier. The effects of chitosan with different bisguanidine contents on DNA-binding capacity, biocompatibility, and inflammation inhibition were compared, revealing that chitosan containing 20% bisguanidine (BGC2) was found to have the best overall performance. In vitro, BGC2 effectively cleared cfDNA and inhibited the production of inflammatory factors. BGC-MN made from BGC2 had good mechanical and solubility properties. In vivo, BGCMNs cleared cfDNA, reduced the level of inflammatory factors in the dermis, and exerted a good therapeutic effect on mice with psoriasis. These results suggested that BGC-MNs provided a new approach to treating psoriasis in terms of scavenging cfDNA and exerting anti-inflammatory effects.