Purpose <p>A trifold prehabilitation program that integrates exercise, nutritional support, and psychological care has not yet been incorporated into routine care for leukemia patients prior to induction chemotherapy. This study aimed to evaluate the safety and feasibility of this trifold intervention and to further examine its potential impact on physical fitness, nutritional risk, and psychological health.</p> Methods <p>In a single-blind, parallel-group randomized trial, 86 newly diagnosed leukemia patients at a tertiary hospital in China were randomly assigned to a 12-week prehabilitation group (<i>n</i> = 43) or usual care (<i>n</i> = 43). Primary outcomes were recruitment, attrition, and safety. Secondary outcomes included the 6-min walk test (6MWT), exercise self-efficacy, cancer-related fatigue (CRF), anxiety, depression, and nutrition. Assessments occurred at baseline (T0), pre-chemotherapy (T1), and 1 (T2) and 3&#xa0;months (T3) post-chemotherapy.</p> Results <p>The recruitment rate was 60.14%, with an attrition rate of 20.93%, and no serious adverse events occurred. Compared with controls, the intervention group showed significantly greater improvements in 6-min walk distance and cancer-related fatigue from T1 to T3 (all <i>p</i> &lt; 0.05). Improvements in exercise self-efficacy were significant at T2 and T3 but not at T1. Nutritional status improved at T3 (<i>p</i> = 0.033). Anxiety and depression levels were consistently lower across all follow-up points (<i>p</i> &lt; 0.01).</p> Conclusions <p>This study demonstrates that prehabilitation is safe, feasible, and potentially beneficial for physical, nutritional, and psychological outcomes in leukemia patients.</p> Trial registration <p>China Clinical Trials Registration Platform: ChiCTR2500105061, date of registration: June 27, 2025 (retrospectively registered).</p>