OBJECTIVE: To systematically analyze the efficacy and safety of interleukin (IL)-12/23, IL-17, and selective IL-23 inhibitors in moderate to severe plaque psoriasis. METHODS AND RESULTS: Twenty-four randomized placebo-controlled trials were included. Compared to placebo, risk ratios (RR) of achieving PASI-75 and PGA/IGA 0/1 respectively were 20.20 (95% CI 13.82-29.54, p < .00001) and 14.55 (10.42-20.31, p < .00001) for ustekinumab 90 mg, 13.75 (8.49-22.28, p < .00001) and 9.81 (5.70-16.89, p < .00001) for ustekinumab 45 mg, 17.65 (12.38-25.17, p < .00001) and 26.13 (16.05-42.53, p < .00001) for secukinumab 300 mg, 15.36 (10.76-21.94, p < .00001) and 20.91 (12.82-34.13, p < .00001) for secukinumab 150 mg, 18.22 (10.63-31.23, p < .000001) and 18.82 (10.36-34.16, p < .00001) for ixekizumab 80 mg every 4 weeks, 19.83 (11.07-35.52, p < .00001) and 20.41 (11.01-37.81, p < .00001) for ixekizumab 80 mg every 2 weeks, 14.79 (9.86-22.16, p < .00001) and 21.93 (15.52-31.01, p < .00001) for brodalumab 210 mg, 11.55 (7.77-17.18, p < .00001) and 16.59 (11.72-23.49, p < .00001) for brodalumab 140 mg, 12.40 (8.87-17.34, p < .00001) and 10.84 (7.91-14.85, p < .00001) for guselkumab 100 mg, 11.45 (7.45-17.58, p < .00001) and 10.97 (6.44-18.69, p < .00001) for tildrakizumab 200 mg, 11.02 (7.17-16.93, p < .00001) and 10.03 (6.45-15.59, p < .00001) for tildrakizumab 100 mg. Similar outcomes were seen for PASI-90. Safety was satisfactory for each therapy at any dose, but a slightly increased risk of withdrawal due to toxicity was observed in individuals receiving ixekizumab compared to placebo. CONCLUSION: Ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, and tildrakizumab were highly efficacious and generally well-tolerated when used as treatments for moderate to severe plaque psoriasis.