Abstract Background Psoriasis is a chronic inflammatory skin disease often associated with obesity and metabolic dysfunction, which may worsen disease severity. Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, have shown metabolic and anti-inflammatory effects, but their impact on psoriasis in non-diabetic patients with obesity remains unclear. Objective To evaluate the effects of a six-month semaglutide treatment on psoriasis severity and clinical, metabolic, inflammatory, and psychosocial parameters in patients with psoriasis and obesity. Methods In this prospective cohort study, 43 patients received weekly semaglutide along with lifestyle counseling. Psoriasis severity (PASI), quality of life (DLQI), depressive symptoms (BDI), nutritional ultrasound, and biochemical markers were assessed baseline and after six months. Correlations between PASI improvement (ΔPASI) and baseline variables and their changes were analyzed, adjusting for age and weight loss. Results After six months, participants showed significant reductions in PASI (–48%), BMI, preperitoneal and superficial fat, along with improvements in DLQI, BDI, and metabolic markers. Baseline disease severity, depressive symptoms, insulin resistance, and preperitoneal fat were negatively associated with PASI improvement. These associations remained significant after adjustment (e.g., HOMA-IR, r = –0.82; preperitoneal fat, r = –0.66). ΔPASI was most strongly correlated with reductions in superficial fat (r = 0.89), DLQI (r = 0.55), and BDI (r = 0.51). Changes in BMI and glycemic markers were not significantly associated after adjustment. Conclusions In patients with psoriasis and obesity, semaglutide improves both skin disease and systemic health. The clinical benefit appears associated with specific fat loss and psychosocial improvement, beyond overall weight reduction.