Background: Oxycodone, which is one of the most commonly used opiates in postoperative pain management, has a different affinity for mu-opioid receptors (MOR), kappa-opioid receptors (KOR), and delta-opioid receptors (DOR). Accumulating research has suggested that neurotrophins (NTs) are involved in opioid analgesia. In the current exploratory study, we aimed to investigate the underlying mechanisms of the analgesic effects of oxycodone on post-surgery pain in rats and to determine whether neurotrophic factors and receptors were involved in these effects. Methods: Mechanical and thermal sensitivity tests were used to evaluate the validity of the postoperative pain rat model and to determine the analgesic effect of oxycodone. Quantitative PCR and Western blot analysis were used to detect the changes in the expression of three types of opioid receptors and NTs and their high-affinity receptors in the spinal cord after surgery and oxycodone administration. Results: Oxycodone showed an analgesic effect on plantar incision (PI)-induced hyperalgesia, especially thermal hyperalgesia. We detected an obvious increase in MOR expression levels but insignificant changes in KOR and DOR levels in the spinal cord after PI. Moreover, we found that oxycodone was able to reverse the increased expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tyrosine kinase receptor (TrK) A, and TrkB and the decreased expression of NT-3 and TrkC, after PI. Pretreatment with oxycodone also altered the expression of these mediators. Conclusion: Based on the results, possible underlying mechanisms for the antinociceptive properties of oxycodone in acute postoperative pain include the activation of MOR downstream signaling and the regulation of NTs and receptor expression through attenuation of glial activation and fortification of antinociceptive mediators in the spinal cord. This study may provide new insights into the molecular mechanisms underlying the analgesic action of oxycodone.