Abstract This experiment examined the effects of a synbiotic supplement (yeast-derived prebiotic + Bacillus subtilis probiotic), which replaced or was fed with feed-grade antimicrobials (monensin and tylosin), on performance and health responses of feedlot cattle. Angus-influenced steers (n = 192) from 4 different sources were weaned and transported 800 km to an experimental feedlot. Steers arrived on d 0 and a shrunk body weight (BW) was recorded. Steers were then ranked by source and shrunk BW and allocated to 1 of 24 drylot pens (8 steers/pen). Steers a received free-choice diet of 3 treatments: 1) monensin and tylosin (RT; 360 mg/steer/day from Rumensin and 90 mg/steer/day from Tylan; Elanco Animal Health, Greenfield, IN), 2) yeast-derived ingredient and B. subtilis probiotic (CC;8 g∙steer-1∙day-1 of Celmanax and 28 g∙steer-1∙day-1 of Certillus; Church and Dwight Co., Inc., Princeton, NJ), or 3) a combination of RT and CC (RTCC). Animals were adapted to diets in a stepwise manner which consisted of a receiving diet (d 0 to 56), two step-up diets (step-up: d 57 to 63; step-up 2: d 64 to 70), and a final diet (d 71 to slaughter). The cattle were slaughtered in four groups according to BW and balanced by treatments. More specifically, 33 steers were slaughtered on d 200, 33 steers on d 230, 63 steers on d 257, and 63 steers on d 285. Upon slaughter, hot carcass weight, backfat thickness, Longissimus muscle area, USDA marbling score, USDA yield/quality grades, and liver abscess score were recorded. Overall, feed intake during the duration of the experimental period (d 0 to slaughter) was greater (P < 0.01) in CC compared with RT and RTCC. However, no differences were observed for ADG (P = 0.61), final BW (P = 0.67), or morbidity (P = 0.15). With increases in intake but no differences in ADG the CC group had lower feed efficiency (P = 0.02) when compared with RT and RTCC. Upon slaughter, CC had higher marbling scores compared with RT (P = 0.04). Both the CC and RTCC cattle had larger Longissimus muscle area (P = 0.07) and more carcasses grading choice or better (P < 0.01) when compared with RT. Whereas, hot carcass weight, backfat thickness, and yield grade did not differ among treatments (P ≥ 0.20). There was tendency observed for liver abscesses (P ≤ 0.09) to be greater in CC compared with RT and RTCC. Overall, supplementing feedlot steers with RT and CC improved feed intake and some carcass measures despite the decreased feed efficiency experienced by these cattle but combining CC and RT did not yield any additional performance or health benefits.