Background <p>Liposomal bupivacaine (LB) provides prolonged analgesia, but it remains unclear whether it prevents rebound pain or merely delays its onset. This study investigated the effect of LB on rebound pain in a mouse model of peripheral nerve block to determine whether its resolution results in a pain response exceeding that of unblocked controls.</p> Methods <p>Methylene blue staining was employed to compare the success rate of nerve stimulator-guided versus anatomical landmark-based techniques for combined sciatic and femoral nerve blockade.Postoperative rebound pain following liposomal bupivacaine administration under nerve stimulator guidance was assessed at multiple time points using von Frey and Hargreaves tests. Histological analyses of perineural inflammation and Wallerian degeneration were conducted on postoperative days 2 and 28.</p> Results <p>Nerve stimulator-guided blocks had high success rates (sciatic: 93.3%, <i>P</i>=0.035; femoral: 73.3%,&#xa0;<i>P</i>=0.030).LB extended thermal (24h,&#xa0;<i>P</i>&lt;0.05) and mechanical (36h,&#xa0;<i>P</i>&lt;0.05) analgesia. Transient thermal rebound pain occurred at 48h (<i>P</i>=0.003), but no mechanical rebound was observed. LB group showed significantly more severe Wallerian degeneration and Neural inflammation in both the sciatic and femoral nerves compared to the S group at day 2 (<i>P</i>&lt;0.05).</p> Conclusions <p>Liposomal bupivacaine did not prevent rebound pain but merely delayed its onset in a mouse model of combined sciatic and femoral nerve block.</p>