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HBeAg seroclearance represents a critical milestone in the treatment of HBeAg-positive chronic hepatitis B (CHB), which is closely associated with disease remission, functional cure, and reduced hepatocellular carcinoma risk. As HBeAg is a secreted viral protein associated with active HBV replication, infectivity, and host immune tolerance, its disappearance usually indicates a transition toward improved immune control rather than simple loss of a laboratory marker. This review comprehensively explores the immunological mechanisms underlying HBeAg seroclearance, thoroughly examines its impact on the natural course of CHB and systematically analyzes the regulatory roles of antiviral drug efficacy, host immune status, and viral genotypes in HBeAg clearance. Integrating updated guidelines and evidence-based research, we propose optimized strategies for managing HBeAg-negative CHB, including goal setting, treatment cessation criteria, and long-term monitoring protocols. Our findings emphasize that HBeAg clearance not only signifies virological suppression but also reflects the dynamic equilibrium of host immune responses, thereby providing both theoretical foundation and practical support for achieving functional cure and reducing HCC risk in CHB patients.