Simple SummaryCancer-related fatigue affects the majority of people undergoing chemotherapy for cancer. The Mediterranean Diet provides healthy macro- and micronutrients that promote energy production and counter known mechanisms that contribute to fatigue. Thus, we designed a Mediterranean Diet program specifically for patients undergoing chemotherapy that included food provision, education, a cookbook, and weekly telephone check-ins. In a two-arm randomized controlled trial (n = 33), we found that our program was safe and feasible; there was excellent adherence (>70%) to the Mediterranean Diet. The Mediterranean Diet program led to less fatigue to a small-moderate degree at weeks 4 and 8. For those with a lower Mediterranean Diet score before the program, the program had a larger effect. Mitochondria are the cellular organelles that produce ATP energy and, in circulating T cells, fatigue was associated with mitochondrial dysfunction. These data support larger studies testing how and how much a Mediterranean Diet during chemotherapy can alleviate fatigue.Cancer-related fatigue is a common, burdensome symptom of cancer and a side-effect of chemotherapy. While a Mediterranean Diet (MedDiet) promotes energy metabolism and overall health, its effects on cancer-related fatigue remain unknown. In a randomized controlled trial, we evaluated a rigorous MedDiet intervention for feasibility and safety as well as preliminary effects on cancer-related fatigue and metabolism compared to usual care. Participants had stage I–III cancer and at least six weeks of chemotherapy scheduled. After baseline assessments, randomization occurred 2:1, MedDiet:usual care. Measures were collected at baseline, week 4, and week 8 including MedDiet adherence (score 0–14), dietary intake, and blood-based metabolic measures. Mitochondrial respiration from freshly isolated T cells was measured at baseline and four weeks. Participants (n = 33) were 51.0 ± 14.6 years old, 94% were female, and 91% were being treated for breast cancer. The study was feasible, with 100% completing the study and >70% increasing their MedDiet adherence at four and eight weeks compared to baseline. Overall, the MedDiet intervention vs. usual care had a small-moderate effect on change in fatigue at weeks 4 and 8 (ES = 0.31, 0.25, respectively). For those with a baseline MedDiet score <5 (n = 21), the MedDiet intervention had a moderate-large effect of 0.67 and 0.48 at weeks 4 and 8, respectively. The MedDiet did not affect blood-based lipids, though it had a beneficial effect on fructosamine (ES = −0.55). Fatigue was associated with mitochondrial dysfunction including lower basal respiration, maximal respiration, and spare capacity (p < 0.05 for FACIT-F fatigue subscale and BFI, usual fatigue). In conclusion, the MedDiet was feasible and attenuated cancer-related fatigue among patients undergoing chemotherapy, especially those with lower MedDiet scores at baseline.