Childhood and adolescent obesity are growing global health concerns, with genetic factors playing an important role. Despite the increasing prevalence of obesity in India, monogenic obesity remains underdiagnosed. We report 2 cases of early-onset morbid obesity due to melanocortin-4 receptor (MC4R) gene mutation. Case 1 was a 5-year-old boy who presented with severe hyperphagia and rapid weight gain since infancy. Case 2 was a 12-year-old girl who presented with progressive obesity, hyperphagia, and bilateral genu varum. Both patients exhibited severe insulin resistance with no syndromic stigmata. Genetic analysis confirmed a homozygous MC4R mutation in both cases. They were managed with a multidisciplinary approach that included dietary modification, structured physical activity, and pharmacotherapy using the glucagon-like peptide-1 analog liraglutide and metformin. Both cases showed a satisfactory response to liraglutide. These case reports highlight the point at which monogenic obesity can be clinically suspected and distinguished from syndromic obesity. Moreover, they underscore the role of genetic testing for monogenic obesity and the targeted therapies in its management.