Objective To observe the clinical efficacy and adverse drug reactions of apatinib combined with tegio in the second-line treatment of advanced esophageal cancer. Methods Seventy-two patients with advanced esophageal cancer from January 2018 to December 2019 in the Tumor Center of the No. 901 Hospital of Chinese People's Liberation Army Joint Logistics Support Force were selected as research objects. According to the random number table method, the patients were divided into control group (n=36) and observation group (n=36). Patients in the control group were given irinotecan combined with tegio regimen chemotherapy, irinotecan 160 mg/m2, intravenous drip on the first day; tegio 50-60 mg orally each time, twice a day, oral administration for 2 weeks, discontinuation for 1 week, 3 weeks for 1 cycle. Patients in the observation group were given tegio with the same administration method and dosage as the control group, and apatinib 0.5 g orally each time, once a day, continuous oral administration, 3 weeks for 1 cycle. Patients of the two groups were treated for 4 cycles. The primary study endpoints were objective response rate (ORR) and disease control rate (DCR). The secondary study endpoints were median overall survival (mOS), median progression-free survival (mPFS), quality of life scores and incidences of adverse drug reactions. Results After 4 cycles of treatment, the ORR and DCR in the observation group were 38.89% (14/36) and 63.89% (23/36) respectively, which were higher than those in the control group [16.67% (6/36) and 38.89% (14/36)], and there were statistically significant differences (χ2=4.431, P=0.035; χ2=4.503, P=0.034). The Karnofsky performance status score and special scale for esophageal cancer QLQ-OES24 score in the observation group were 75.23±10.65 and 76.55±9.12 respectively, which were higher than those in the control group (66.15±10.31 and 65.36±9.01), and there were statistically significant differences (t=7.285, P=0.018; t=7.613, P=0.015). The incidences of oral mucositis, hand-foot syndrome, hypertension, proteinuria and rash in the observation group were 38.89% (14/36), 50.00% (18/36), 25.00% (9/36), 11.11% (4/36) and 33.33% (12/36) respectively, which were higher than those in the control group [11.11% (4/36), 13.89% (5/36), 0 (0/36), 0 (0/36), 2.78% (1/36)], and there were statistically significant differences (χ2=7.407, P=0.007; χ2=10.797, P=0.001; χ2=10.286, P=0.001; χ2=4.235, P=0.040; χ2=11.359, P=0.001). The incidences of gastrointestinal reactions and bone marrow suppression in the observation group were 41.67% (15/36) and 30.56% (11/36) respectively, which were lower than those in the control group [66.67% (24/36) and 55.56% (20/36)], and there were statistically significant differences (χ2=4.531, P=0.033; χ2=4.589, P=0.032). There were no patients who withdrew due to severe adverse reactions.The mOS and mPFS of the patients in the observation group were 11.6 months and 8.1 months respectively, which were longer than those in the control group (8.9 months and 5.6 months), and there were statistically significant differences (χ2=8.015, P=0.012; χ2=8.721, P=0.007). Conclusion Apatinib combined with tegio in the second-line treatment of patients with advanced esophageal cancer can effectively prolong the survival time of patients, improve patients' quality of life, and the adverse reactions are tolerable.