Plaque psoriasis is an immune-mediated chronic recurrent skin disease. In recent years, 308 nm excimer laser (308 nm EL) and topical tacrolimus have been widely used to treat psoriasis. The purpose of this study was to evaluate the efficacy of 308 nm EL irradiation combined with 0.1% tacrolimus ointment in the treatment of plaque psoriasis. This study was a retrospective observational study involving 100 patients with plaque psoriasis, divided into two groups: the control group (50 cases) was treated with 0.1% tacrolimus ointment; the observation group (50 cases) was treated with 308 nm EL and 0.1% tacrolimus ointment. After eight weeks of treatment, the psoriasis area and severity index (PASI) of the two groups were compared, and the occurrence of adverse reactions during treatment was recorded. Before treatment, there was no significant difference in PASI scores between the two groups (p > 0.05). However, the PASI scores of the two groups were significantly lower after treatment than before treatment, and the PASI scores of the observation group after treatment were lower than those of the control group (p < 0.05). No serious adverse reactions occurred in either group. 308 nm EL irradiation combined with 0.1% tacrolimus ointment could be considered a safe and effective method for the treatment of plaque psoriasis, which can significantly reduce the PASI score and is more effective than the use of 0.1% tacrolimus ointment alone, and it is expected to be popularized in the clinic.