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Given ongoing uncertainty about the benefits and harms of prostate-specific antigen (PSA) screening, this systematic review updates the evidence to inform guideline recommendations for adults aged ≥ 18 years in primary care. We searched multiple bibliographic databases from inception to 30 May 2022, with an update on 24 July 2024, for randomized controlled trials (RCTs) and comparative observational studies evaluating PSA-based screening with or without adjunctive technologies such as magnetic resonance imaging (MRI). Studies were selected in duplicate, with data extraction and quality assessment verified by a second reviewer; risk of bias and evidence certainty were assessed using study design-specific tools and GRADE. Four RCTs and one cohort study (17 articles) were included: ERSPC, PLCO and CAP compared PSA screening with no screening, while STHLM3-MRI evaluated a risk-based test combined with MRI targeted biopsy. Meta-analysis showed 0.96 fewer prostate cancer deaths per 1000 individuals invited to screen, corresponding to a 12% relative reduction over 9.5-22 years (RR 0.88, 95% CI 0.81-0.95). One trial estimated 2.3% to 10.3% overdiagnosis over 10-14 years. Overall certainty of evidence was low or very low. PSA screening may offer a small mortality benefit, but uncertainty and variable harms limit confidence, underscoring the need for high-quality evidence, particularly for MRI and risk-based screening strategies.