The negative rate of serum HBV DNA, HBeAg, and ALT in the tenofovir group was significantly higher than that in the entecavir group (86.67%, 3.33%, and 80.00%) (all P < 0.05 ). In the tenofovir group, 2cases were considered. Objective. The aim of this study is to analyze the clinical effect and safety of tenofovir in the treatment of chronic hepatitis B (CHB) patients. Methods. A total of 60 patients with CHB who were admitted and treated in Anqing First People’s Hospital Affiliated to Anhui Medical University from January 2019 to July 2020 were randomly assigned at a ratio of 1 : 1 into the tenofovir group (treated with tenofovir) and the entecavir group (treated with entecavir) via the random number table method. The clinical therapeutic effect and safety of the two groups were compared. Results. The serum hepatitis B virus (HBV) DNA levels in the two groups decreased after treatment, but there was no significant difference. Ths (2.50%) had nausea, 1 (1.25%) had headache, and 0 had an elevated creatine kinase. In the tenofovir group,1(3.33%) had nausea, 0 had headache, and 0 had an elevated creatine kinase. In the entecavir group, there were 3 (10.00%) cases of nausea, 2 (6.67%) cases of headache, and 1 (3.33%) case of elevated creatine kinase. The overall incidence of adverse reactions in the tenofovir group (3.33%) was significantly lower than that in the entecavir group (20.00%) (all P < 0.05 ). Conclusion. Tenofovir is more effective than entecavir in the treatment of patients with CHB due to low incidence of adverse events and a good safety profile.