Context Atherosclerosis is a systemic pro-inflammatory and pro-oxidative disease, accounting for approximately a third of deaths globally. It has been proposed that omega-3s, through their antioxidant and anti-inflammatory properties, mitigate atherosclerotic disease progression. However, due to the systemic pro-inflammatory and pro-oxidative state of atherosclerosis, it is proposed that patients with atherosclerotic disease may have higher omega-3 requirements than the average requirement, due to increased nutrient utilization in anti-inflammatory and anti-oxidant processes. Objective The aim of this review was to determine what dose and duration of omega-3 supplementation is required to reach a therapeutic blood level of omega-3s (eicosapentaenoic acid ≥150 µg/mL or omega-3 index ≥8%) in people with chronic atherosclerotic disease. Data Sources This systematic review comprehensively searched MEDLINE, Emcare, Scopus, and CINAHL using key search terms for atherosclerotic disease, omega-3, supplementation, and blood levels of omega-3s. Data Extraction Two reviewers independently screened 529 randomized controlled trials (RCTs) supplementing omega-3s in patients with chronic atherosclerotic disease. Data Analysis In total, 25 journal articles from 17 original RCTs were included and assessed quantitatively. Supplementation at 1.8 g to 3.4 g per day for a 3-month–6-month duration, and at 4.4 g and above for as little as 1 month–6 months were identified as the most effective dosage ranges for increasing blood levels of omega-3s to therapeutic levels in people with atherosclerotic disease. Conclusions Consideration should be given to routine omega-3 supplementation and to increasing the omega-3 dietary recommendations and upper limits of daily intake to improve clinical outcomes and reduce the risk of cardiac mortality in this population.