Between-set rest intervals (RIs) may influence accumulated fatigue, work volume, and therefore oxygen uptake (VO2) and energy expenditure (EE) during resistance training. The study investigated the effects of different RIs on VO2 and EE in resistance exercises performed with multiple sets and recruiting large and small-muscle mass. Ten healthy men performed 4 randomized protocols (5 sets of 10 repetitions with 15 repetition maximum workloads in either horizontal leg press [LP] or chest fly [CF] with an RI of 1 and 3 minutes). The VO2 was measured at rest, within sets, and during 90-minute postexercise recovery (excess postexercise oxygen consumption [EPOC]). The EE was estimated from VO2net (total VO2 - rest VO2). The VO2 increased in all protocols, being higher within the exercises and during EPOC in the LP than in the CF regardless of the RI. The 1-minute RI induced higher accumulated VO2 during LP (p < 0.05) but not during CF. The EPOC lasted approximately 40 minutes after LP1, LP3, and CF1, being longer than after CF3 (20 minutes, p < 0.05). Total EE was mainly influenced by muscle mass (p < 0.001) (LP3 = 91.1 ± 13.5 kcal ∼ LP1 = 88.7 ± 18.4 kcal > CF1 = 50.3 ± 14.4 kcal ∼ CF3 = 54.1 ± 12.0 kcal). In conclusion, total VO2 was always higher in LP than in CF. Shortening RI enhanced the accumulated fatigue throughout sets only in LP and increased VO2 in the initial few minutes of EPOC, whereas it did not influence total VO2 and EE in both exercises. Therefore, (a) the role of RI in preventing early fatigue seems to be more important when large-muscle groups are recruited; (b) resistance exercises recruiting large-muscle mass induce higher EE because of a greater EPOC magnitude.