<p>The management of postoperative pain is a critical ethical concern and a challenge in laboratory animal research, particularly for mice. Surgical procedures are routinely conducted in mice, but the use of analgesic drugs is underreported and the assessment of their efficacy is limited. This systematic review assesses the efficacy of analgesic drugs for postoperative pain in mice, addressing the influence of various factors, including sex, surgical invasiveness, pain modalities and analgesic classes. A systematic literature search resulted in 48 eligible studies included in the qualitative analysis and 43 in the quantitative analysis. The overall pooled standardized mean difference (SMD) for analgesic drugs was 0.46 (95% confidence interval 0.31 to 0.60), indicating a positive pain-reducing effect. Subgroup analysis revealed that analgesic treatment was significantly more effective in male (SMD 0.84; 0.60 to 1.08) than in female mice, in mild (SMD 0.57; 0.38 to 0.75) than in severe surgical procedures and in reducing evoked pain (SMD 1.12; 0.83 to 1.41) than in reducing spontaneous pain. In addition, almost all analgesic drug classes tested, including opioids, nonsteroidal anti-inflammatory drugs, acetaminophen and local anesthetics were effective in reducing evoked pain but not spontaneous pain (SMD 0.12; −0.03 to 0.27). However, most studies present limitations that could produce a high risk of bias. Taken together, our results indicate that, although analgesic drugs can reduce postoperative pain in mice, their efficacy is reduced in females, severely invasive surgeries and spontaneous pain. Thus, high-quality studies are still needed to answer ethical concerns and to guarantee full analgesia in laboratory mice submitted to surgical procedures.</p>