ObjectiveThe objectives of the study were to compare the clinical efficacy and adverse effects of two analgesic protocols consisting of bupivacaine liposome injectable solution (BLIS) and 0.5% bupivacaine and fentanyl for postsurgical analgesia in dogs undergoing limb amputation.Study designRandomized, double‐blind, prospective, controlled, intent‐to‐treat, clinical noninferiority trial.AnimalsForty client‐owned dogs.MethodsDogs undergoing amputation were randomly assigned to either the BLIS or control group. Postoperative pain, sedation, nausea, and amount eaten were assessed using appropriate scales at 6, 12, 18, and 24 h by trained individuals blinded to the treatment protocol. Rescue analgesia was provided for Glasgow composite measure pain scale (short form) (CMPS‐SF) scores of 5 or above. Clients were requested to pain score their dogs at home using a visual analogue scale (VAS) for 48 h following discharge.ResultsForty dogs completed this study (20 control dogs and 20 BLIS dogs). The BLIS and control groups were equivalent for sedation, nausea, amount eaten, and pain, at all time periods except at 6 h (p < .01), when the BLIS group pain score was lower.ConclusionThe BLIS provided equivalent analgesia with fewer adverse effects than fentanyl constant rate infusion (CRI) following limb amputation. Rescue analgesia was provided to five dogs in the BLIS group and four in the control group, and there was no statistical difference. Nausea scores did not differ statistically.Clinical significanceAs BLIS provides equivalent analgesia, this may allow for decreased reliance on opioids in the immediate postoperative period.