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Abstract Background Caring for hemodialysis patients could be a heavy burden on family caregivers, causing them to become fatigued and decrease their quality of life. This study aimed to investigate whether Jacobson’s relaxation can help alleviate the fatigue of family caregivers of hemodialysis patients. Methods This randomized controlled trial was conducted in 2021. Sixty-six family caregivers of hemodialysis patients were recruited by convenience sampling from a referral hospital in Tehran, Iran, and assigned randomly by coin toss to two groups of experimental (n = 32) and control (n = 34). Caregivers in the experimental group performed Jacobson’s relaxation three times a week, each time for 30–45 min, for 30 days. The score and severity of fatigue before, 2 weeks after, and 1 month after the intervention were measured with the Fatigue Severity Scale. Data analysis was performed in the statistics software SPSS using descriptive statistics (frequency, percentage, mean, and standard deviation) and analytic statistics (Independent Samples t-test, Mann–Whitney U test, Chi-Square test, Fisher’s exact test, and RM-ANOVA test). The significance level was less than 0.05. Results The fatigue scores of the experimental and control groups were not significantly different before the intervention (4.42 ± 0.42 vs. 4.38 ± 0.42, P = 0.696). However, the experimental group had significantly lower fatigue scores than the control group 2 weeks after the intervention (4.11 ± 0.63 vs. 4.39 ± 0.42, P = 0.036) and 1 month after the intervention (3.5 ± 0.71 vs. 4.4 ± 0.44, P = 0.001). The results also showed a significant drop in the fatigue score of the experimental group after the intervention (P