Retinal vein occlusion (RVO) shares key pathophysiological pathways with metabolic and atherothrombotic disorders. Emerging evidence suggests that statins and antidiabetic drugs may be associated with lower RVO incidence, yet their potential to modify RVO risk remains uncertain. A systematic search of MEDLINE, Embase, Scopus, and Web of Science was performed from inception through June 11, 2025, for studies evaluating the association between systemically administered antidiabetic or lipid-lowering agents and RVO. Risk of bias was assessed using the Newcastle-Ottawa Scale. Association between antidiabetic or lipid-lowering therapy and RVO risk was the primary outcome, and drug-class-specific associations, differences by RVO subtype, and related retinal outcomes were the secondary outcomes. Certainty of evidence was appraised. Protocol registered in PROSPERO (CRD420251077729). Ten good-quality studies (six cohorts and four case-control) involving over 2 million adults met eligibility criteria. Meta-analysis results suggest that statin use consistently reduced RVO risk; pooled effect odds ratio (OR) = 0.65 (95% CI = 0.53-0.79; I[2] = 29%) with moderate certainty. Studies suggest metformin monotherapy halved risk [hazard ratio (HR) = 0.46, 0.30-0.73], and glucagon-like peptide-1(GLP-1) receptor agonists were associated with reduced risk compared to dipeptidyl-peptidase-4 (DPP-4) inhibitors (HR = 0.73, 0.54-0.98). Findings for sodium-glucose cotransporter-2 (SGLT-2) inhibitors were inconsistent, showing harm versus other oral glucose-lowering drugs in 1 Korean study (HR = 1.26, 1.06-1.51) but benefit versus DPP-4 inhibitors in a Taiwanese study (HR = 0.76, 0.59-0.98). Other conventional agents (repaglinide, thiazolidinediones, sulfonylureas, α-glucosidase inhibitors, insulin) yielded imprecise or null estimates. Only statins met criteria for meta-analysis; findings for other drug classes were narratively synthesised from single studies. Statins show moderate evidence of an association with reduced RVO risk. Signals of benefit for metformin and GLP-1 receptor agonists arise from single large cohorts and require independent replication. Additionally, the role of SGLT-2 inhibitors remains uncertain. These indicators warrant confirmation in prospective studies and may inform tailored retinal vascular risk reduction strategies in patients with diabetes and dyslipidaemia.