Purpose Acute ingestion of a ketone monoester, with and without co-ingestion of carbohydrate, was investigated for effects on running economy (RE), time to exhaustion (TTE), and other related indices of endurance running performance. Methods Using a three condition, placebo-controlled, randomized crossover design, 11 male middle- and long-distance runners ran at five submaximal speeds (10–14 km·h−1) on a motorized treadmill for 8 min each, immediately followed by a ramp test to volitional exhaustion. Participants consumed either a 10% carbohydrate solution (CHO), a 10% carbohydrate solution with 750 mg·kg−1 body mass of an (R)-3-hydroxybutyl (R)-3-hydroxybutyrate ketone monoester (CHO + KE), or 750 mg·kg−1 body mass of the ketone monoester in flavored water (KE) before (two-thirds of the dose) and during (one-third of the dose) exercise. Results β-hydroxybutyrate concentration averaged 1.8 ± 0.3 and 2.1 ± 0.3 mM during exercise in CHO + KE and KE, respectively. RE was lower at each submaximal running speed (effect size = 0.48–0.98) by an average of 4.1% in KE compared with CHO, but not between CHO + KE and CHO. TTE did not differ between CHO (369 ± 116 s), CHO + KE (342 ± 99 s), or KE (333 ± 106 s) (P = 0.093). Conclusions Acute ingestion of a ketone monoester without carbohydrate, but not when coingested with carbohydrate, improved RE in middle- and long-distance runners at a range of submaximal running speeds and did not alter TTE in a short-duration ramp test to volitional exhaustion. Further investigation is required to examine if these differences translate into positive performance outcomes over longer durations of exercise.