Objective The aim of the study was to investigate the efficacy and adverse effects of olanzapine in the treatment of moderate to severe refractory neuropathic pain.Methods Forty patients with digestive system cancer were enrolled, who had moderate to severe refractory neuropathic pain; the patients were treated with olanzapine for 2 weeks at a daily dosage of 5 mg to 10 mg per night according to patients' response and tolerability, combined with conventional analgesic therapy. Pain intensity was evaluated by using a Numeral Rating Scale (NRS) at baseline, 3 days, and 2 weeks after therapy. The Pittsburg Sleep Quality Index (PSQI) was evaluated at baseline and 2 weeks after therapy. Data on adverse events were recorded. The dosage of conventional analgesics was adjusted over time based on the severity of pain. Results The mean pain score decreased by 2.575 ± 1.318 (P < 0.000) at 3 days and by 3.400 ± 1.614 (P < 0.000) at 2 weeks; 30％ of the patients experienced significant pain relief at 3 days and 50％ at 2 weeks. The PSQI decreased by 4.725 ± 2.828 (P < 0.000) at 2 weeks. The adverse events induced by olanzapine included sleepiness, weight gain, dizziness, fatigue, dry mouth, and constipation; all the side effects were mild. Conclusion When combined with conventional analgesic therapy, olanzapine was effective in relieving pain and sleep disturbance, and was well-tolerated among patients with refractory neuropathic pain.