Objective Many rheumatologists are inundated with questions about what “natural remedies” and “anti-autoimmune diets” exist for decreasing Systemic Lupus Erythematosus (SLE) disease activity. Over the last three decades, there has been an abundance of data from several different trials about omega-3 fatty acids sourced from fish oil, but the findings have been contradictory. This review seeks to present this data so that evidence-based recommendations can be given to patients, supporting the use of an adjuvant regimen with their present immunosuppression. Methods A literature search was conducted using the PubMed, Google Scholar, MEDLINE, and Scopus electronic databases to retrieve relevant articles for this review. Trials conducted on human subjects with SLE with full publications in English were included from 1 January 1980 to 1 April 2021. The impact of fish oil-derived omega-3 fatty acid supplementation on specific clinical features, the innate and adaptive immune response, biomarkers, and disease activity measures were assessed. The initial search yielded 7519 articles, but only 13 met our criteria and were eligible for this review. Results Data from thirteen articles were assessed. Ten trials assessed disease activity as an outcome, with eight trials demonstrating an improvement in patients in the omega-3 fatty acid group as assessed by a validated clinical tool or individual patient criteria. There was a significant improvement in Systemic Lupus Activity Measure-Revised (SLAM-R) scores at week 12 ( p = .009) and week 24 ( p < .001). Additionally, a reduction of urinary 8-isoprostane, a non-invasive marker of disease activity, was observed. There was no treatment benefit seen with respect to renal parameters such as serum creatinine or 24-hour urine protein; or systemic parameters such as C3, C4, or anti-double stranded DNA (anti-dsDNA) levels regardless of the dose of the omega-3 LUPUS fatty acids or duration of the trial. Conclusion While there is conflicting evidence about the benefits of omega-3 fatty acid supplementation on SLE disease activity, specific measures have demonstrated benefits. Current data show that there is a potential benefit on disease activity as demonstrated by SLAM-R, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and British Isles Lupus Assessment Group (BILAG) scores and plasma membrane arachidonic acid composition and urinary 8-isoprostane levels, with minimal adverse events.