The cost of walking and running on uneven terrain is not directly explained by external mechanical work. Although metabolic cost of transport increases linearly with gradient at uphill and downhill gradients exceeding 15%, at shallower gradients, the relationship is nonlinear, with the minimum cost occurring at ~10% downhill grade. Given these nonlinear relationships between grade and metabolic cost, we projected a significant difference in the total metabolic cost of two walking conditions that required the same total external mechanical work be performed over the same total period of time; in one condition, time was spent walking to gradients that were fixed at þ 10.5% and -10.5% and in the other condition time was spent walking to gradients that varied from 0 to þ 21% and from -21 to 0%. We compared these two conditions experimentally, using an approach to quantify nonsteady-state oxidative energy expenditure. In line with our projection, the “variable” grade condition resulted in an 8.3 ± 2.2% higher total cumulative oxidative energy expenditure (J·kg-1) compared with the “fixed” grade condition (P < 0.001). Future work should aim to apply our approach across different gradients, speeds, and forms of locomotion; especially those that might provide insight into how humans optimize locomotion on variable grade routes.