<p>This study presents a comprehensive and novel assessment of organochlorine pesticide (OCP) in the Meghna River of Bangladesh using liquid–liquid extraction coupled with gas chromatography-electron capture detector (GC-ECD). The study investigated 20 legacy OCPs in this major transboundary river, addressing a critical knowledge gap, particularly given the absence of systematic monitoring and increasing industrial and agricultural pressures on the basin. Surface water from ten strategically selected locations was analyzed. The concentrations were observed for 4,4′-DDE (BDL–4.217 µgL⁻¹), 4,4′-DDD (BDL–3.141 µgL⁻¹), endrin aldehyde (BDL–4.373 µgL⁻¹), <i>trans</i>-chlordane (0.009–0.363 μgL⁻¹), and methoxychlor (BDL–2.510 µgL⁻¹), with elevated levels near industrial and agricultural sites. The analytical method demonstrated strong performance, with recoveries (75.26–107.80%), LOD (0.290–0.834 µgL⁻¹), LOQ (0.878–2.527 µgL⁻¹), and excellent linearity (<i>R</i>² = 0.990–0.998) with three times replications. While most OCPs were under USEPA/WHO thresholds, the presence of 4,4^/-DDE and 4,4^/-DDD at several sites indicates historical DDT use and ongoing environmental persistence. Health risk assessment revealed elevated non-carcinogenic risks, particularly for 4,4′-DDD (hazard quotient = 1.81 via ingestion; 24.70 via dermal contact), exceeding USEPA thresholds. Combined exposure yielded hazard indices of 2.05 (oral) and 28.07 (dermal), indicating potential long-term health concerns. Carcinogenic risks from 4,4′-DDE and 4,4′-DDD (incremental lifetime cancer risk, 10⁻⁵–10⁻⁴) surpassed acceptable limits (1 × 10⁻⁶). Comparisons with global data revealed higher OCPs than regulated systems but lower levels than some developing regions, suggesting ongoing legacy contamination. Overall, the study’s novelty lies in its systematic evaluation of previously underreported OCPs in the Meghna River and its relevance to guiding regulatory action in Bangladesh.</p>