Schizophrenia poses a significant burden on global health systems and societies. Atypical antipsychotics like clozapine and quetiapine have been shown to be effective in schizophrenia treatment. The most recent head-to-head systematic review comparing clozapine and quetiapine was conducted over a decade ago, and its findings remained inconclusive due to the limited number of high-quality, adequately powered trials. An updated synthesis is therefore warranted. A systematic search was carried out in the Cochrane Schizophrenia Group's Study-Based Register of Trials to identify all double-blind, randomized controlled trials comparing clozapine with quetiapine in schizophrenia and related disorders in terms of efficacy and safety. Risk ratios were calculated and mean differences for binary and continuous outcomes respectively, were assessed using the random effects model. Risk of bias was assessed for included studies and a Summary of findings table created using the GRADE approach. One short-term study involving 63 adults with first-episode schizophrenia fulfill the inclusion criteria, where the overall risk of bias was unclear due to missing reports. No significant differences were observed in global state, relapse, metabolic effects, and general mental state. Clozapine was associated with more somnolence, hypersalivation, and constipation. Other adverse effects and early discontinuation did not significantly differ. Clozapine and quetiapine appear to have similar efficacy in schizophrenia treatment with distinct adverse effect profiles. More high-quality RCTs are needed to confirm efficacy equivalence and clarify safety differences between clozapine and quetiapine, providing the robust evidence required to support safer and more appropriate prescribing practices.