The recreational use of fentanyl (FT) combined with xylazine (XZ), known as “tranq-dope,” poses a growing public health threat due to its high toxicity and mortality. This study evaluated the effectiveness of naloxone (NX), its lipophilic prodrug NX90, and their combinations with the κ-agonist/µ-antagonist nalbuphine (NB) in reversing overdose and restoring respiratory function in a rat model. At the low FT dose (0.052 mg/kg), adding XZ (1 mg/kg) shortened time to overdose by ~2,600 seconds compared with FT alone, whereas onset times were similar at medium and high FT doses. Respiratory rate at overdose was also higher with XZ, showing a 2.2-fold increase at high FT doses. Most interventions did not significantly shorten time to reversal. Only NX+NB in females and NX90+NB in both sexes reduced reversal time compared with NX alone. However, respiratory rate at reversal was significantly improved with NX+NB, ½NX90+NB, and NX90+NB (90–92 breaths/min) compared with naloxone alone (80 ± 6 breaths/min). Interventions containing nalbuphine (κagonist/µantagonist) yielded higher RR and HR at reversal than NX alone, suggesting a contribution of κagonism to physiological recovery. In this FT+XZ dose range, coadministration of xylazine (1 mg/kg) was associated with higher respiratory rates at the time of overdose onset across ascending fentanyl doses, blunting the dosedependent RR decline observed with fentanyl alone at that specific endpoint. Comparable or improved reversal outcomes could be achieved using half-doses of NX or NX90 with NB—potentially reducing total dose of naloxone and mitigating the risk of precipitated withdrawal in individuals with opioid use disorder.