The decline of physical function during chemotherapy predicts poor quality of life and premature death. It is unknown if resistance training prevents physical function decline during chemotherapy in colon cancer survivors. This multicenter trial randomized 181 colon cancer survivors receiving postoperative chemotherapy to home-based resistance training or usual care control. Physical function outcomes included the short physical performance battery (SPPB), isometric handgrip strength, and the physical function subscale of the Medical Outcomes Short-Form 36-item questionnaire. Mixed models for repeated measures quantified estimated treatment differences (ETD). At baseline, subjects had a mean (SD) age of 55.2 years (12.8); 67 (37%) were ≥60 years, and 29 (16%) had a composite SPPB score ≤9. Compared with control, resistance training did not improve the composite SPPB score [ETD: -0.01 (95% CI: -0.32, 0.31); P = 0.98], or the SPPB scores for balance [ETD: 0.01 (95% CI: -0.10, 0.11); P = 0.93], gait speed [ETD: 0.08 (95% CI: -0.06, 0.22) P = 0.28], and sit-to-stand [ETD: -0.08 (95% CI: -0.29, 0.13); P = 0.46]. Compared with control, resistance training did not improve isometric handgrip strength [ETD: 1.50 kg (95% CI: -1.06, 4.05); P = 0.25] or self-reported physical function [ETD: -3.55 (95% CI: -10.03, 2.94); P = 0.28]. The baseline SPPB balance score [r=0.21 (95% CI: 0.07, 0.35)] and handgrip strength [r=0.23 (95% CI: 0.09, 0.36)] correlated with chemotherapy relative dose intensity. Among colon cancer survivors with relatively high physical functioning, randomization to home-based resistance training did not prevent physical function decline during chemotherapy. NCT03291951.