Objective: To explore and analyze the clinical efficacy and incidence of adverse reactions of entecavir combined with long-acting interferon in treating hepatitis B. Methods: The study was conducted from January 2020 to December 2022, and the research subjects were 69 hepatitis B patients admitted to our hospital. The patients were divided into a research group (n = 35) and a control group (n = 34). Patients in the control group were treated with entecavir, while patients in the study group were treated with entecavir combined with long-acting interferon. The antiviral efficacy, liver function indicators, clinical effectiveness, and incidence of adverse reactions were compared between the two groups. Results: The HBV-DNA negative conversion rate and HBeAg seroconversion rate of the patients in the study group were higher than those of the control group, and the virological breakthrough rate was lower than that of the control group (P < 0.05); the alanine transaminase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) levels of the patients in the study group were all lower after treatment. In the control group, the albumin (ALB) level was higher than that in the control group (P < 0.05). The clinical effective rate of patients in the study group was higher than that in the control group (P < 0.05); there was no significant difference in the incidence of adverse reactions between the two groups (P > 0.05). Conclusion: The treatment effect of entecavir combined with long-acting interferon in patients with hepatitis B is significant. It can effectively antiviral and improve the liver function of patients. The incidence of adverse reactions is low and can be promoted and applied.