This study aims to research whether there is a difference in cardiorespiratory variables and gross mechanical efficiency (GE) in healthy individuals during low-intensity one-legged and two-legged exercise on the combined arm–leg (Cruiser) ergometer and whether motor learning occurs. The outcome of this study will support the use of the Cruiser ergometer in future as a testing and training instrument in the rehabilitation of patients with a lower limb amputation. Twenty-eight healthy men participated in this randomized-controlled trial. One group (n=14) used one leg and both arms during the exercise and the other group (n=14) used both legs and both arms. All participants performed a 1-day low-intensity exercise protocol. This included a standardized pretest and post-test of three bouts of 4 min exercise at 40 W and an exercise intervention of seven bouts of 2×4 min exercise at 40 W. The one-legged and two-legged group differed significantly in the heart rate and GE between the pretest and post-test. At the post-test, the one-legged group showed motor learning. GE improved significantly in both groups over the duration of the three exercise bouts of the pretest, but it did not improve during the post-test. There are differences in cardiorespiratory variables and GE between one-legged and two-legged exercise on the Cruiser ergometer. When using this ergometer in the rehabilitation of patients with a lower limb amputation, it is important to consider these differences and the occurrence of motor learning.