Introduction: The pathophysiology of endometriosis-induced pain is complex and current pain management is often inadequate. As a consequence, the quality of life of endometriosis patients is reduced due to persistent and often recurrent severe pain, affecting emotional well-being. Case description: In this case report, we present a 28-year-old patient with deep endometriosis and severe pain resistant to conventional therapy, who experienced, after an 8-h infusion with esketamine, no pain symptoms for 8 weeks. Discussion: Current treatment options to suppress chronic pain symptoms in patients with (deep) endometriosis are often inadequate. Esketamine targets key components of the condition (inflammation, pain, depression), but the use of this drug in the treatment of chronic pain due to endometriosis has not been reported yet. Future trials are necessary to assess the effect of esketamine in the treatment of chronic pain due to endometriosis. Conclusion: This case report highlights the potential of esketamine infusion therapy in the treatment of endometriosis patients with persistent pain despite conventional therapy.