<p>Sepsis survivors frequently experience prolonged fatigue, which impacts their quality of life. This study aimed to investigate the effects of the program reducing fatigue among sepsis survivors. This single-blind randomized controlled trial included 68 sepsis survivors at a tertiary hospital in Bangkok. Participants were randomized into experimental (<i>n</i> = 34) and control (<i>n</i> = 34) groups and evaluated at three time points: baseline, 2 weeks and 4 weeks into the program. The experimental group received a 4-week program involving exercise, mindfulness, nutritional education, and sleep hygiene via the Line application. Fatigue was measured using the Piper Fatigue Scale-12 (PFS-12). Statistical analysis was performed using repeated measures analysis of variance. Baseline fatigue scores did not significantly differ between the groups. The experimental group had a significantly lower mean score for fatigue in week 4 than at baseline (F = 1510.790, <i>p</i> &lt; 0.001). Between-group comparisons showed significant differences in fatigue scores at all time points, particularly in week 4 (F = 1003.66, <i>p</i> &lt; 0.001 and F = 527.695, <i>p</i> &lt; 0.001, respectively). However, the experimental group had a lower mean fatigue score than the control group. The 4-week program significantly reduced fatigue among sepsis survivors.</p><p>Trial registration: Thai Clinical Trials Registry https//www.thaiclinicaltrials.org/show/TCTR20240329002. The registration number is TCTR20240329002. The date of registration is 12/03/2024.</p>