Identifying signaling pathways that induce B cell response can aid functional cure strategies for chronic hepatitis B infection (CHB). TLR8 activation with ssRNA was shown to enhance follicular helper T cell (T_FH) function leading to improved B cell responses in vitro. We investigated whether this mechanism can rescue an exhausted immune response in CHB infection. Effect of TLR8 agonism on supporting cytokines and T_FH and B cells were evaluated using ex vivo and in vitro assays. The ability of an oral TLR8 agonist to promote T_FH and B cell response was tested in samples from phase 1b clinical trial. TLR8 agonism induced T_FH polarizing cytokine IL-12 in monocytes. Treatment of peripheral blood mononuclear cells (PBMCs) from CHB patients with TLR8 agonists induced cytokine IL-21 by T_FH cells with enhanced IL-21⁺BCL-6⁺ and ICOS⁺BCL-6⁺ co-expression. Mechanistically, incubation of isolated naïve CD4⁺ T cells with TLR8 triggered monocytes resulted in their differentiation into IL-21⁺ICOS⁺BCL-6⁺ T_FH in an IL-12 dependent manner. Furthermore, co-culture of these IL-21 producing T_FH with autologous naïve B cells led to enhanced memory (CD19⁺CD27⁺) and plasma B cell generation (CD19⁺CD27⁺⁺CD38⁺) and IgG production. Importantly, in T_FH from CHB patients treated with an oral TLR8 agonist, HBsAg-specific BCL-6, ICOS, IL-21 and CD40L expression and rescue of defective activation induced marker (AIM) response along with partial restoration of HBsAg-specific B cell ELISPOT response was evident. TLR8 agonism can thus enhance HBV-specific B cell responses in CHB patients by improving monocyte-mediated T_FH function and may play a role in achieving HBV functional cure.