The safety and efficacy of the esketamine-based opioid-sparing anesthesia protocol, though validated, are understudied in robotic surgeries. This study used robot-assisted nephrectomy in Bama miniature pigs to explore its application. Six healthy Bama miniature pigs were randomly assigned to esketamine group (K) and control group (C). In Group K, based on the anesthetics of Group C, 0.5 mg/kg esketamine was used for anesthesia induction, and anesthesia was maintained with 0.5 mg/kg·h esketamine. Results showed Group K exhibited more stable hemodynamics intraoperatively, particularly at 5 min after the start of surgery and at the time of extubation (p < 0.05). Dosages of propofol (250 ± 8.7 mg vs. 347 ± 6.1 mg), sufentanil (12.3 ± 0.6 µg vs. 25 ± 1.0 µg) and remifentanil (498.3 ± 27.5 µg vs. 828.3 ± 20.2 µg) in group K were significantly reduced(p < 0.001). Recovery times for eyelid reflex (22.0 ± 2.0 min vs. 28.0 ± 2.6 min), extubation (24.7 ± 2.5 min vs. 32.3 ± 2.5 min), and righting reflex (37.7 ± 2.5 min vs. 48.7 ± 5.5 min) were significantly shorter in group K (p < 0.05). In conclusion, the esketamine-based opioid-sparing anesthesia protocol can be safely and effectively used in Bama miniature pigs undergoing robot-assisted nephrectomy.