The aim of this retrospective clinical study was to compare the combinations of ketamine/diazepam (KD group) and tiletamine/zolazepam (TZ group) for the induction of general anaesthesia in horses undergoing elective surgery. The data from the clinical and the anaesthetic records of 138 horses from 2021 to 2023 were evaluated, and the horses were divided in two groups: KD (n = 60) and TZ (n = 72). The horses were premedicated with romifidine and methadone IV; anaesthesia was induced with ketamine/diazepam for the KD group and tiletamine/zolazepam for the TZ group and was maintained with isoflurane and a constant rate infusion of romifidine. The data encompassed sex and neuter status, age, breed, weight, American Society of Anaesthesiologists physical status, type of surgical procedure performed under anaesthesia, induction time, induction score, surgery time, recovery time, and the recovery score using a descriptive scale. Baseline heart rate (HR), intraoperative HR, baseline respiratory rate (fR), intraoperative fR, mean arterial pressure (MAP), oxygen saturation (SpO2), and fraction of expired isoflurane (FE’Iso) were also recorded. The induction time was significantly longer (p = 0.004) in the TZ group (60 (40–120)) as compared to the KD group (50 (30–120)). Recovery time was also significantly longer (p ≤ 0.001) in the TZ group (46.5 (15–125)) as compared to the KD group (30 (5–105)). These findings suggested that, in adult horses undergoing elective surgery, TZ could be considered a valid alternative to KD for the induction of general anaesthesia. Additional experimental studies comparing the two induction regimens and their pharmacokinetic and pharmacodynamic characteristics are needed.