: Chronic kidney disease-associated pruritus (CKD-aP) is a common symptom in hemodialysis patients. A frequent and intense itching sensation largely torments patients, impacts quality of life outcomes, and it has an independent association with mortality. The objective of this study is to investigate the effects of oral supplementation with omega-3 polyunsaturated fatty acid (omega-3 PUFA) on circulating interleukin-6 (IL-6), cardiometabolic parameters, skin moisturization, and the consequent symptoms of pruritus in hemodialysis patients. : Volunteers on maintenance hemodialysis with very severe pruritus symptoms were enrolled in this prospective cohort study. Subjects were instructed to consume 1000 mg fish oil once daily for 3 months. Pruritus scoring, skin moisture, plasma IL-6, and cardiometabolic parameters were measured at baseline, and at the first, second, and third month post-supplementation with fish oil for assessment of the clinical significance. : A total of 27 patients who had a mean age of 67.33 ± 11.06 years and 3.98 ± 3.23 years on hemodialysis completed the study. Supplementation with omega-3 PUFA significantly decreased IL-6 levels ( < 0.001), but increased the levels of c-reactive protein (CRP) ( < 0.05). Evaluation of the cardiovascular risk showed significant (all < 0.001) decreases in the total cholesterol (CHO), low-density lipoprotein (LDL), and triglycerides (TG) levels, and an increase in the high-density lipoprotein (HDL) level. A significant decrease in plasma creatinine (CR) was observed ( < 0.001), but the decrease was limited. Supplementation with omega-3 PUFA significantly improved (all < 0.001) skin hydration on both the face and arms, as well as disease-related symptoms of pruritus. Conclusion: Omega-3 PUFA supplementation improved inflammation, renal function, cardiovascular parameters, dry skin conditions, and the consequent symptoms of pruritus in hemodialysis patients.