Abstract Background Polyunsaturated fatty acid (PUFA) supplementation has been reported to improve disease activity in inflammatory rheumatic diseases (IRDs). However, data are often conflicting and studies insufficiently large to draw conclusions. This systematic literature review and meta-analysis aimed to better estimate the effect of oral supplementation with omega (n)-3 and n-6 PUFA on IRD activity in terms of duration, dose, type, and source.Methods The literature was searched in PubMed, EMBASE, and Cochrane Library databases up to October 2020. Studies were reviewed in accordance with PRISMA guidelines. The effect of PUFA supplementation on disease activity was expressed as the standardized mean difference (95% CI). Metaregression and subgroup analyses involved type of IRD, Jadad score, PUFA source (animal or vegetable), and doses.Results We obtained 42 references; 30 randomized controlled studies were included comparing the effects of PUFA versus control on disease activity (710 IRD patients receiving PUFA supplementation and 710 controls, most with rheumatoid arthritis). We found a significant improvement in pain, swollen and tender joint count, Disease Activity Score in 28 joints, and Health Assessment Questionnaire score in IRD patients receiving PUFA supplementation as compared with controls, with a significant decrease in erythrocyte sedimentation rate but not C-reactive protein level. Although meta-regression revealed no difference by IRD type or source or dose of PUFA supplementation, subgroup analysis revealed more parameters significantly improved with animal- than vegetable-derived PUFAs and 3- to 6-month supplementation. Most studies examined high-dose supplementation (>2 g/day).Conclusion PUFA consumption, especially omega-3 from animal source >2 g/day, may improve IRD activity and might be an adjuvant therapy in rheumatoid arthritis.Trial registration The protocol was registered at PROSPERO ( CRD42021253685 ).