Background. Psoriasis is an immune-mediated, chronic inflammatory disease, and genetic, immune, oxidative stress (OS), and environmental factors are all thought to contribute to its occurrence. Proanthocyanidins (PCs) are natural flavonoids consisting of catechins and epicatechins which have anti-inflammatory and anti-OS activities. PCs have been widely used to treat various diseases, but reports regarding psoriasis are rare. Objective. To investigate the therapeutic effect and potential mechanisms of action of PCs in a psoriasis-like mouse model. Methods. Thirty male BALB/c hairless mice were assigned to six groups ( n = 5 ): normal, model, low-dose PCs, medium-dose PCs, high-dose PCs, and control groups. The final five groups were dorsally exposed to 5% imiquimod (IMQ) cream once a day for 6 consecutive days, while the normal group received no intervention. Following the first day of IMQ application, mice in the PC-treated group were dosed with different amounts of PCs daily by oral gavage for six days, whereas mice in the control group received normal saline in the same way. One week later, skin lesions were evaluated by the severity of scoring system based on psoriasis area and severity index (PASI), and pathological alterations were assessed by hematoxylin-eosin (HE) staining. Indicators of inflammation or OS, such as interleukin- (IL-) 17, IL-23, phosphorylated-phosphatidylinositol 3-kinase (p-PI3K), phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), catalase (CAT), vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), and heme oxygenase-1 (HO-1), were determined by ELISA, RT-PCR, western blot, and immunohistochemistry (IHC) analysis. Results. IMQ administration induced the formation of large dark red plaques with thickly layered scales on the dorsal skin of mice; nevertheless, the lesions were substantially alleviated by PC administration. Histopathological alterations were observed in both model and control groups with epidermal hyperkeratosis, granulosa layer thinning, acanthosis, downward extension of rete ridges, dermal papillae expansion, capillary hyperplasia, and infiltration by inflammatory cells around blood vessels. These pathological changes, however, were restored by a range of doses of PCs, high-dose PCs in particular. Different doses of PCs significantly lowered the spleen index, levels of inflammatory or oxidative proteins (IL-17, IL-23, MDA, ROS, p-PI3K, and p-STAT3), and the mRNA expression of Il-17, Il-23, Vegf, and iNos. Protein and mRNA levels of anti-OS and anti-inflammatory biomarkers, including SOD, CAT, GSH, and HO-1, greatly increased after PC treatment, especially at the highest dose. Conclusions. Our findings reveal that PCs ameliorate psoriasis-like symptoms, suppressing the inflammatory response and mitigating OS damage in an IMQ-induced psoriasis-like mouse model. These effects are probably related to the inactivation of STAT3 and PI3K and activation of HO-1 signaling.