In latest years, extensive outburst of abundant infectious ailments across the world has created chaos between the populations. Chiefly, the residents in the tropical and sub-tropical areas are concerned by these virulent pathogens. In spite of the development in significant elementary acquaintance regarding a variety of pathogens, the existing chemotherapy is still unacceptable as a result of imperfect effectiveness, long-term action, high cost, and unwanted side-effects. Natural products and synthetic compounds have been found to express numerous pharmacological activities. The present review article focuses on the therapeutic perspectives of chalcone based natural compounds in exhibiting anti-viral activity against rhino virus, human immunodeficiency virus (HIV), influenza virus, polio virus, dengue virus, and tobacco mosaic virus (TMV) by modulating vital therapeutic targets like HIV-1 protease, DEN-1 NS3 protease, and neuraminidase. These natural compounds serve as interesting leads for synthetic drug fabrication by various drug design, drug discovery, and drug development approaches as well as structure activity relationships (SARs) predictions. These compounds from nature may serve as templates for further exploration of molecular targets, structural biology, mechanism of actions (MOAs), etc.