Methods: Sixty patients undergoing TFESI were randomized to receive inhaled methoxyflurane or placebo before the procedure. Pain intensity was assessed using the Visual Analog Scale (VAS) at multiple time points during and after TFESI. Secondary outcomes included patient and physician satisfaction, as well as the incidence of adverse events. Renal and hepatic function parameters were evaluated pre- and post-procedure to assess safety. Results: The methoxyflurane group reported significantly lower worst pain scores during TFESI compared to placebo (3.33±0.70 vs. 5.71±1.23, p <0.01), with sustained pain relief for up to 60 minutes post-procedure. Adverse events in the methoxyflurane group were mild and self-limiting (dizziness, nausea/vomiting, and dry mouth), occurring in 10% of patients. No significant between-group differences were observed in renal or hepatic function indices. Patient satisfaction was significantly higher with methoxyflurane (96.67%) than with placebo. Conclusions Inhaled methoxyflurane is a safe and effective analgesic for TFESI, offering significant procedural pain reduction and high patient satisfaction, while maintaining a favorable safety profile.