Cancer-related fatigue is a prevalent, debilitating symptom that contributes to increased health care utilization among hospitalized patients. Music therapy is a nonpharmacological intervention that uses active (eg, singing, selecting songs) and passive (eg, listening) techniques. Preliminary evidence from small trials suggests a potential benefit for cancer-related fatigue in the inpatient setting; however, it remains unclear which techniques are most effective. A cross-sectional mixed-methods study was performed to compare cancer-related fatigue before and after active or passive music therapy. Cancer-related fatigue was captured via the Edmonton Symptom Assessment Scale fatigue item. Patients were asked to provide postsession free-text comments. A total of 436 patients (mean [standard deviation] age, 62.2 [13.4] years; n = 284 [65.1%] women; n = 294 [67.4%] white; active music therapy n = 360 [82.6%]; passive music therapy n = 76 [17.4%]) with a range of primary malignancies participated. Active music therapy was associated with a 0.88-point greater reduction in cancer-related fatigue (95% CI, 0.26 to 1.51; P = .006; Cohen's D, 0.52) at postsession as compared with passive music therapy when restricting the analysis to patients who rated their baseline cancer-related fatigue as moderate to severe (ie, ≥ 4; n = 236 [54.1%]). Free-text responses confirmed higher frequencies of words describing positive affect/emotion among active music therapy participants. In a large sample of inpatient adults with diverse cancer disease types, active music therapy was associated with greater reduction in cancer-related fatigue and increased reporting of positive affect/emotions compared with passive music therapy. Additional research is warranted to determine the specific efficacy and underlying mechanisms of music therapy on cancer-related fatigue.