Researchers sought to assess the strength of the relationship between fatigue severity and avoidance in people with chronic disease for a study. The databases PubMed, PsycINFO, CINAHL, and ProQuest Dissertations and Theses were searched. In chronic disease samples, eligible studies measured fatigue and avoidance. There were 66 studies in total. Rstudio was used to analyze the data. A random-effects model was used for fatigue severity and avoidance, and weighted mean effect size was calculated. Mixed-effects meta-regression analyses were performed to investigate moderating variables such as patient, clinical, and measurement characteristics. The funnel plot, trim-and-fill, and p-curve investigated publication bias. The meta-analysis included 71 distinct patient samples from 66 studies. The total number of participants included was 13,024. A small, positive relationship between fatigue severity and avoidance was discovered (r(71)=0.22, P<.001), 95% CI [0.18–0.27], SE=0.02 (Q(70)=349.96, P<.001), indicated significant heterogeneity. In moderator analyses, age, gender, illness duration, avoidance type, and disease sample were all non-significant. Regarding publication bias, trim-and-fill produced a modified weighted mean effect size (r(83)=0.18, P<.001), and a p-curve analysis supported the current analysis’s evidential value. The findings support the notion that fatigue severity and avoidance are positively associated in people with chronic disease, which has implications for behavioral interventions in this population.