Psoriasis is a chronic inflammatory disease that is debilitating, particularly in its more severe forms. Multiple systemic therapies are used in moderate-to-severe psoriasis, but the development of biological interventions has revolutionized its management and improved its outcomes. To compare the effectiveness and safety of the different biological interventions approved for use in moderate-to-severe plaque psoriasis. Multiple databases were searched for relevant articles and a prospectively planned network meta-analysis was conducted on randomized controlled trials that assessed biological treatments in moderate-to-severe psoriasis. The search yielded 84 trials that encompassed 39,798 patients. Infliximab 5mg/kg had the highest probability of achieving 75% reduction on PASI scale in comparison to placebo (RR = 18.76, 95% CI [12.31; 28.57], high certainty), while Ixekizumab 80mg and Brodalumab 210mg had the highest probability at achieving PASI90 and PASI100 (37.81, [28.57; 50.03] and 81.04, [26.16; 251.01], respectively, with moderate certainty) On the other hand, Risankizumab 150mg and Ustekinumab 90mg were the only regimens with significantly less withdrawal rates due to adverse events (0.41, [0.18-0.96], and 0.57, [0.35-0.91], respectively with High certainty) compared to placebo. Anti-IL17 and Infliximab were among the most effective in ameliorating the symptoms of psoriasis, however, anti-IL17 were better at achieving full or almost full improvement on the PASI scale. Real life decision-making is not so clear-cut and should remain patient centered, taking into consideration factors such as safety, comorbidities, biologic naivety, dosing preferences and insurance considerations.