Invasive plant species often have negative impacts on agriculture and society in addition to their detrimental effects on biodiversity and environment. It is important to assess such impacts to devise effective management plans. A field survey study was carried out to assess the socio-economic effects of a highly invasive plant species, parthenium weed (Parthenium hysterophorus L.) across the three different cropping regions in Punjab province of Pakistan. The farming communities of different cropping regions reported significant effects of parthenium weed on their crop and livestock production, health and social well-being. The mixed cropping region was heavily infested and most affected region, whereas the cotton–wheat region was least affected. Farmers were well-aware of parthenium weed presence, its biology, habitat, and mode of dispersal across the landscape. All the major crops cultivated were infested by varying degrees of weed densities with potato, sugarcane and maize being the most infested crops. Farmers were generally good at managing the weed in crops which cost them significant amounts of money (ca. $205 per household). Parthenium weed also infested the fodder collection and grazing sites affecting the livestock production negatively. Each farmer lost an additional ca. $935 annually due to the weed infestations on fodder collection sites. A significant proportion of farmers also reported negative effects of the weed on animal health (22–36%) and human health (14–24%). The average annual costs associated with animal health and human health were ca. $2031 and $73 per household, respectively. Despite acknowledging the value of weed management in non-cropped areas, fewer farmers managed it practically in such areas. Most farmers reported parthenium weed as a very difficult-to-manage weed. About 37% of farmers were willing while 60% were likely to participate in a potential management program in future. A comprehensive management strategy is urgently needed to address the looming crisis of parthenium weed invasion across the province and similar approach must be implemented at the national and international level.