Background: Psoriasis is an immune-mediated chronic skin disease that is associated with a significant psychological burden. A newer line of therapy is represented by biologic agents. Our study aimed to evaluate the effect of biologic therapies in the treatment of psoriasis concerning both disease severity and psychological comorbidity. Material and Methods: We performed a prospective case-control comparison to evaluate the prevalence of depression and anxiety in psoriasis patients and unaffected individuals. All patients were recruited between October 2017 and February 2021. Baseline depression (PHQ-9), anxiety (GAD-7), PASI, and DLQI scores were noted. Then, we evaluated the efficacy of biologic treatment in reducing these scores at 6 months of therapy. Patients were treated with either ixekizumab, secukinumab, guselkumab, certolizumab, ustekinumab, risankizumab, or adalimumab. Results: 106 bio-naïve patients with psoriasis and 106 controls without the disease were included in this study. Depression and anxiety were significantly more common among psoriasis patients than in unaffected individuals (p< 0.0001). Female patients presented both depression and anxiety more frequently than men in both case and control groups. Disease severity was significantly associated with worsened depression and anxiety symptoms. Biologic therapy resulted in a significant decrease in all four scores at the 6-month mark for each patient (p< 0.0001). Only an improved PASI correlated significantly with lower depression and anxiety scores (p< 0.005), whereas a decreased DLQI did not (p> 0.955). None of the seven biologic agents used was discovered to be superior. Conclusion: biologic therapies are effective in decreasing both disease severity and alleviating depression and anxiety symptoms in psoriasis.