This study quantifies the impacts of climate change on yields and the corresponding economic losses in six relevant crops that account for 65% of the harvested area in Mexico and are highly relevant in terms of consumption and economic value. The results show that crop yields could decrease considerably during this century, especially in the rainfed management system. Under a high-emission scenario, large reductions in yields are expected by the end of this century for both rainfed and irrigated management systems of maize (42%, 31.4%), rice (51.4%, 41.3%), sorghum (41.1%, 36.6%), soybean (59.1%, 44.9%), wheat (23.3%, 20.0%), and rainfed sugarcane (11.7%). At the national level, the present value of losses in the selected crops amounts to $37,934 million dollars, which represents about twice the current total national agricultural production of Mexico. Rainfed agriculture represents about 69% of these losses and reductions in maize yields account for almost 70% of the total losses. States such as Veracruz, Sinaloa, Tamaulipas, and Jalisco represent half of the total economic losses. However, about 16% of the aggregated losses occur in states with high levels of poverty and subsistence farming like Chiapas, Oaxaca, and Guerrero. Climate change will significantly increase the risks that already vulnerable subsistence farmers’ face in the present. Although ambitious mitigation efforts can reduce the estimated impacts in most of the crops, residual damages are considerable, and the prompt implementation adaptation strategies is required.