Objectives The aim of this study was to compare the sedative effects in cats administered acepromazine–nalbuphine and acepromazine–butorphanol, intramuscularly (IM) and intravenously (IV), and the occurrence of adverse cardiorespiratory effects. Methods Forty-six cats were randomly divided into four groups and administered acepromazine (0.05 mg/kg) combined with nalbuphine (0.5 mg/kg) or butorphanol (0.4 mg/kg), IV (ACP-NALIV and ACP-BUTIV groups, respectively) or IM (ACP-NALIM and ACP-BUTIM groups, respectively). Sedation scores, ease of intravenous catheter placement (simple descriptive scale [SDS] scores), physiologic variables, venous blood gases and the propofol dose required for anesthetic induction were recorded. Results Mild sedation was observed in all groups approximately 30 mins after treatment administration (timepoint T1, prior to propofol administration). Sedation scores at T1 increased above baseline in all groups ( P <0.05), but no significant difference was observed among groups. Dynamic interactive visual analogue scale sedation scores (range 0–100 mm) recorded at T1 were (median [interquartile range]): ACP-NALIM, 12 (10–12); ACP-NALIV, 11 (6–16); ACP-BUTIM, 11 (7–14); and ACP-BUTIV, 12 (7–19). Overall, SDS scores did not change from baseline at T1 and there was no significant difference among groups. The propofol dose did not differ among groups. Blood gases remained within the reference intervals for cats. Significant decreases from baseline were detected for all groups in systolic arterial pressure (SAP). Mean ± SD values at T1 were (mmHg): ACP-NALIM, 108 ± 13; ACP-NALIV, 102 ± 10; ACP-BUTIM, 97 ± 13; and ACP-BUTIV, 98 ± 21. Arterial hypotension (SAP <90 mmHg) was recorded at T1 in 0/11, 1/13, 4/11 and 5/11 cats in groups ACP-NALIM, ACP-NALIV, ACP-BUTIM and ACP-BUTIV, respectively, and was further exacerbated after the induction of anesthesia with propofol. Conclusions and relevance In healthy cats administered acepromazine–nalbuphine and acepromazine–butorphanol, IM and IV, the degree of sedation was mild regardless of the protocol and the route of administration. The main adverse effect observed was a reduction in arterial blood pressure.