Background: Selecting proper postoperative adjuvant therapy is of great importance for prolonging overall survival (OS) of patients with biliary tract cancer (BTC). OS is commonly affected by high rate of postoperative recurrence and metastasis. Purpose: The present study aimed to identify the optimal adjuvant therapy for BTC patients. Method: A comprehensive search was carried out on Pubmed, Web of science, and Embase databases to acquire articles regarding BTC therapy approaches. Subsequently, the hazard ratio (HR) and its 95% confidence intervals (CIs) were applied to evaluate the efficacy of different adjuvant therapy regimens. The GemTc (GemTc.0.8-2) and R (R.3.6.0) software were employed to perform statistical analyses. Result: Data from 22 articles, including 14,646 patients, were quantitatively analyzed. The results showed that in terms of 5-year OS, gemcitabine (GEM) was considered as the optimal adjuvant therapy for BTC compared with chemoradiotherapy (CRT; HR = 0.59; 95% CI = 0.34-0.97), observation (OB; HR = 0.49; 95% CI = 0.33-0.73), and radiotherapy (RT; HR = 0.40; 95% CI = 0.22-0.71). Additionally, 5-fluorouracil (5-FU) exhibited improved efficacy compared with RT (HR = 0.52; 95% CI = 0.29-0.91) and OB (HR = 0.63; 95% CI = 0.43-0.92). When the efficacy of 5-FU was compared with that of GEM, the results showed that 5-FU (HR = 1.29) was more effective than GEM. Furthermore, CRT and RT prolonged positive resection margin (R+)-OS (HR = 0.69; 95% CI = 0.49-1.00) and positive lymph node-(N+)-OS (HR = 0.22; 95% CI = 0.074-0.66) in BTC patients. In terms of median recurrence-free survival (RFS) and 1-year OS, the differences were not statistically significant among different therapeutic interventions. Conclusion: The present study suggested that GEM could be used as a first-line adjuvant therapy for resected BTC patients. Additionally, CRT could be the optimal treatment approach for R+ and N+ patients.