<p>Psoriasis is a chronic inflammatory disease with significant burden. Brodalumab and bimekizumab are effective biologics, but real-world use often involves off-label dosing modifications. This systematic review assesses the efficacy and safety of non-standard dosing regimens in adults with psoriasis. A systematic search of PubMed, Embase, Ovid MEDLINE, and the Cochrane Library was conducted for studies published between January 1, 2014, and February 10, 2026. Eligible studies were randomized controlled trials or open-label studies phase 3 or higher evaluating adults with moderate-to-severe plaque psoriasis treated with off-label dosing of brodalumab or bimekizumab. Pediatric studies and reviews were excluded. Risk of bias and evidence certainty were assessed using RoB2 and GRADE. Twelve studies involving 6,725 participants were included. Brodalumab dose reductions led to 13–20% lower rates of sPGA 0/1 at Week 52 compared to the standard regimen. Brodalumab withdrawal led to relapse within eight weeks, but &gt; 90% regained response after retreatment. No dose-dependent safety trends were observed. Bimekizumab dose escalation improved PASI 90 by &lt; 5% compared to the standard dosing, with slightly higher oral candidiasis rates but no increase in serious adverse events. Median relapse time after withdrawal was 28 weeks. Brodalumab dose reductions reduce short-term efficacy and are not routinely recommended. Bimekizumab dose escalation shows minimal added efficacy outside of high-weight patients. Brodalumab allows for rapid recapture of disease control, and bimekizumab may offer a longer drug-free duration before relapse. Limitations include lack of trials designed specifically for off-label dosing and cross-trial analyses.</p>