The aim of this study was to compare three different anesthetic protocols administered intramuscularly (IM) in cats undergoing elective ovariectomy, while evaluating the quality of sedation, antinociceptive, isoflurane-sparing effect, and analgesia in the intra-operative and post-operative phases. A total of 71 female cats were sedated IM with alfaxalone (3 mg/kg) combined with either butorphanol (0.3 mg/kg), methadone (0.3 mg/kg), or pethidine (5 mg/kg). During surgery, vital parameters were constantly monitored; at the end of the procedure, the quality of recovery was assessed through a specific form and each cat was scored for perceived pain using the UNESP-Botucatu scale for 5 days, and rescue analgesia was provided with buprenorphine IM when indicated. Moreover, differences between two different post-operative resting regimens (hospital kennels vs. home) were also assessed. A significant difference emerged for the amount of IM dexmedetomidine required to achieve an adequate level of sedation for intravenous catheterization, highlighting a greater need in the pethidine group (p = 0.021). There was no significant difference between opioid groups for the requirement of intra-operative rescue analgesia, and the clinical parameters were kept within physiological ranges regardless of the opioid used in premedication. Lastly, differences between the UNESP-Botucatu scores were detected from day 3 to day 5 post-operatively, with lower scores in cats with home resting regimens compared to the hospitalized animals, likely due to the presence of an unfamiliar condition and the absence of a cat-friendly environment.