Buprenorphine is perhaps the most prescribed analgesic for management of postoperative pain in mice. Although various buprenorphine formulations are effective in commonly used immunocompetent mouse strains, a knowledge gap exists regarding its efficacy in immunodeficient mice. Here we used a plantar incision to evaluate the efficacy of 3 buprenorphine formulations for attenuating postoperative mechanical and thermal hypersensitivity in the immunodeficient NSG mouse strain. We also characterized the pharmacokinetics of these formulations over a 72-h period. We hypothesized that all 3 buprenorphine formulations evaluated—the standard preparation and 2 extended-release products (Bup-HCl, Bup-ER, and Bup-XR, respectively)—would attenuate postoperative mechanical and thermal hypersensitivity resulting from a plantar incision in NSG mice. Male and female NSG mice (n = 48) were allocated to 4 treatment groups: saline (0.9% NaCl, 5 mL/kg SC once); Bup-HCl (0.1 mg/kg SC, BID for 2 d); Bup-ER (1.0 mg/kg SC once); and Bup-XR (3.25 mg/kg SC once). Mechanical and thermal hypersensitivity assessments were conducted 24 h before surgery and at 4, 8, 24, 48, and 72 h afterward. All groups of mice showed mechanical and thermal hypersensitivity within the first 24 h after surgery. Behavioral pain indicators (guarding, toe-touching [intermittent partial weight bearing], licking the incision, vocalizations) were observed in some mice from each group at every postoperative time point. Plasma buprenorphine was measured in a separate group of mice and concentrations surpassed the suggested therapeutic level (1.0 ng/mL) for less than 4 h for Bup-HCl, for at least 24 h for Bup-ER, and for 72 h for Bup-XR. Our results indicate that at the dosages studied, these buprenorphine formulations do not adequately attenuate postoperative mechanical and thermal hypersensitivity in the plantar incisional model in NSG mice. These findings support the need for strain-specific analgesic protocols for mice used in research.