Tomato leaf curl New Delhi virus (ToLCNDV) was initially identified in 1995, causing tomato infection. Within 29 years, it rapidly expanded its host range and distribution, causing infections in more than 19 countries and economically important crop families, including Cucurbitaceae, Solanaceae, Malvaceae, Fabaceae, and Euphorbiaceae. There are various traditional ways to control ToLCNDV infection, such as insecticides, insect-proof nets, crop rotation, and sowing resistant varieties. These methods are very effective but also have some flaws, such as being environmentally unfriendly, costly, requiring increased labor, and limited long-term effectiveness. Recently, RNA interference (RNAi) has emerged as a potent molecular approach to control this viral infection by degrading essential viral proteins’ mRNA using cellular enzymes. This chapter highlights the mechanism of action, various applications, and challenges of the RNAi technique in plant protection against viral infection. This book chapter also accommodates the mechanism of action, advantages, and challenges of other molecular methods, such as CRISPR/Cas9 gene editing, virus-induced gene silencing (VIGS), host-mediated RNA silencing (HM-RNAi), and transgenic resistance plant development as potent tools for managing ToLCNDV infection. This book chapter highlights the innovative application of molecular techniques in addressing the challenges of ToLCNDV infection and mitigating food scarcity resulting from crop damage in affected areas.