Background and Purpose: Prolonged viral infections often lead to lymphocyte exhaustion, marked by heightened inhibitory receptor expression like PD-1, compromising host defense mechanisms. Although monoclonal antibodies like anti-PD-1 can alleviate exhausted lymphocytes, their cost limits widespread use. The unexplored potential of chemical checkpoint inhibitors in rejuvenating immune responses prompted our investigation. Experimental Approach: We focused on CCT007093, a Wip1 inhibitor, screened out for its unique ability to concurrently reduce PD-1 and FcγRIIB expression, using a murine model of immune exhaustion induced by chronic hepatitis B virus (HBV) infection. Key Results: CCT007093 treatment to HBV-infected mice resulted in decreased levels of PD-1 expression, resulting in reduced percentages of PD-1+/hi CD4 and CD8 T cells in circulation, spleen, and liver. PD-1 and FcγRIIB expression, alongside the percentages of PD-1+/hi and FcγRIIB+/hi CD19+ B cells in these tissues, were similarly diminished. Moreover, CCT007093-treated intrahepatic lymphocytes exhibited heightened responsiveness to ex vivo activation. Together, serum HBsAg levels were significantly reduced in in treated mice compared to controls. Detailed analysis uncovered p65 NF-κB as the primary activator of T cells and B cells, while YY1 emerged as the key regulator, orchestrating the down-regulation of PD-1 and FcγRIIB gene transcription in response to CCT007093. Conclusions and Implications: Our study highlights CCT007093’s pharmacological efficacy in mitigating immune exhaustion in HBV-infected mice, selectively enhancing adaptive immunity. Beyond antiviral applications, it underscores the prowess of chemical checkpoint inhibitors, exemplified by CCT007093, in alleviating immune exhaustion induced by viruses and potentially in various cancers.