Abstract Weeds pose a serious threat in achieving sustainable and profitable crop production. South Asia, as both a major food-producing and consuming region, needs a linear increase in food grain production. Among the several methods of weed management practice, herbicides are the most cost-effective and timely solution. Rice and wheat are the major staple food crops and the introduction of low-dose high efficacious herbicides, such as pyrazosulfuron-ethyl and sulfosulfuron in rice and wheat, respectively, have the major share in the region. With the continuous use of similar herbicides or application of a limited number of herbicides with a similar mode of action in intensive cropping systems, the evolution of herbicide resistance in many weeds has become a serious concern. With limited options of alternate herbicides, the evolution of cross and multiple resistance has emerged as a major challenge. This review has highlighted the usage of herbicides in South Asian countries, the development of herbicide resistance in major crops of the region, and the possible solutions. The adoption of site-specific integrated weed management in managing both herbicide resistance and weed menace, and location-specific agronomic interventions remains critical. The immense potential of adopting novel technologies, such as the use of economic sensing devices for real-time weed identification and spot-spraying, and early detection of herbicide resistance in weeds and their phenotypes, might offer alternatives of herbicide use for safer and cleaner economies.