The Balsas River Basin (BRB) area is the major source of wild medicinal plants commercially sold in Mexico; thus, the region is important in the conservation of these high-demand resources. We studied wild medicinal plant species extracted from the BRB to document the species richness of traded plants and analyze the commercialization dynamics and socioecological vulnerability. We constructed a database of the medicinal plant species traded in the BRB and we developed a risk index from 14 different ethnobotanical, socioeconomic, and ecological variables to assess the vulnerability of each species. The medicinal flora that are traded in the BRB include 257 species, 176 genera, and 83 families. The use of 91% of these species is unregulated by the government. Tropical deciduous forests contribute the greatest number of taxa (38.5%) and herbs are the most harvested plants (45.9%). Less than 5% of these species are protected by national and international regulations. The highest-risk category primarily consists of tree species with the greatest number of uses and plant structures harvested and sold in the largest number of local and regional markets. Due to high commercial demand in the BRB, intensive harvesting is not compatible with conservation. Therefore, public policies that regulate trade and local practices to protect and preserve medicinal plant species must be developed. These policies should maintain people's livelihoods, especially in regions with high marginalization but great biological and cultural richness, such as the BRB.