BACKGROUND & AIMS: N-3 (omega-3) polyunsaturated fatty acids (n-3-PUFA) have been hypothesized to enhance/maintain skeletal muscle mass, strength, and physical function. We conducted an overview of reviews of n-3 fatty acid monotherapy supplementation and examined whether the evidence supports the effects in healthy young and old adults and clinical populations. METHODS: In line with the PRISMA guidelines, a widely accepted framework for conducting and reporting systematic reviews, we conducted a comprehensive search for systematic reviews (OVID, Embase, Web of Science, SPORTDiscus) reporting the effect of n-3 fatty acid supplementation in our target populations. To ensure the reliability and validity of our findings, the methodological quality of the reviews was assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR) 1, a validated tool for appraising the methodological quality of systematic reviews. RESULTS: Thirty-three systematic reviews met our inclusion criteria: 19 non-oncologic, 11 oncologic, and 3 mixed. In non-oncologic populations, 4 out of 16 reviews showed some evidence that n-3-PUFA supplementation benefitted lean mass, with 3 reviews focusing on older populations. For strength, 1 out of 14 reviews found sufficient evidence in favor, while 3 others reported some evidence of n-3-PUFA ingestion. For physical function, 1 out of 15 reviews found sufficient evidence, and 3 reported some evidence favoring n-3-PUFA use. In oncologic participants, only 1 out of 13 reviews found sufficient evidence that n-3-PUFA improved lean mass. No reviews found sufficient evidence for strength or physical function improvements. CONCLUSIONS: Our analysis indicates limited evidence supporting the effectiveness of n-3-PUFA supplementation in both younger and older healthy adults, as well as clinical populations including oncologic patients, to improve or prevent loss of lean mass. Most systematic reviews concluded that n-3-PUFA supplementation did not significantly affect strength, or studies were inconclusive, and there was no consistent impact of n-3-PUFA supplementation on functional outcome measures. These findings underscore the need for further research to better understand the role of n-3-PUFA in muscle health and to guide clinical practice. Our analysis does not support n-3-PUFA monotherapy for lean mass gain/retention enhancing strength or function in healthy young and older persons, and oncologic populations.