Background Our study aims to explore the effect of serum long non-coding RNA (lncRNA) H19 level on the long-term prognosis of endoscopic keyhole surgery or craniotomy for glioma. Methods A total of 264 glioma patients were selected. Patients were randomly divided into the Craniotomy-high H19 group, the Craniotomy-low H19 group, the Endoscopic keyhole surgery-high H19 group and the Endoscopic keyhole surgery-low H19 group. Results Compared with adjacent tissues (5.19 ± 1.42), H19 level in cancer tissues (7.45 ± 1.60) and serum (6.44 ± 1.57) was significantly increased ( P < 0.05). Compared with serum, H19 level in cancer tissues was significantly increased ( P < 0.05). Pearson correlation analysis found that the relative expression level of serum H19 in glioma patients was positively correlated with cancer tissues ( rPearson = 0.547, P < 0.001), but had no significant correlation with adjacent tissues ( rPearson = 0.126, P = 0.207). The expression of H19 in serum was significantly related to WHO grade ( rPearson = 0.514, P < 0.001). Compared with the Endoscopic keyhole surgery-high H19 group and the Endoscopic keyhole surgery-low H19 group, the survival rate of patients in the Craniotomy-high H19 group (χ2 = 17.115 and log-rank P < 0.001; χ2 = 18.406 and log-rank P < 0.001) and the Craniotomy-low H19 group was significantly reduced (χ2 = 15.007 and log-rank P < 0.001; χ2 = 16.121 and log-rank P < 0.001). Cox regression results showed that serum H19 level, craniotomy and WHO grade were risk factors for glioma. When H19 level was lower than 6.28, the 30-month survival rate of patients with the endoscopic keyhole surgery was 100%. Conclusion For patients with low H19 level (<5.36), both endoscopic keyhole surgery and craniotomy are available, otherwise, endoscopic keyhole surgery is more recommended.