Rheumatic heart disease (RHD) is a post-streptococcal sequela caused by <i>Streptococcus pyogenes</i>. The global burden of disease is high among people with low socio-economic status, with significant cases emerging every year despite global eradication efforts. The current treatment includes antibiotic therapies to target strep throat and rheumatic fever and valve replacement strategies as a corrective measure for chronic RHD patients. Valvular damage and valve calcification are considered to be the end-stage processes of the disease resulting from impairment of the endothelial arrangement due to immune infiltration. This immune infiltration is mediated by a cascade of events involving NLRP3 inflammasome activation. NLRP3 inflammasome is activated by wide range of stimuli including bacterial cell wall components like M proteins and leukocidal toxins like nicotinamide dehydrogenase (NADase) and streptolysin O (SLO) and these play a major role in sustaining the virulence of <i>Streptococcus pyogenes</i> and progression of RHD. In this review, we are discussing NLRP3 inflammasome and its plausible role in the pathogenesis of RHD by exploiting the host-pathogen interaction mainly focusing on the NLRP3 inflammasome-mediated cytokines IL-1β and IL-18. Different therapeutic approaches involving NLRP3 inflammasome inactivation, caspase-1 inhibition, and blockade of IL-1β and IL-18 are discussed in this review and may be promising for treating RHD patients.