Medicinal plants continue to play an important role in healthcare, both in Mexico and around the world. We investigated the relationship between various sociodemographic factors, such as age, economic activity, years of schooling, socioeconomic levels, gender, and language proficiency, and the knowledge and frequency of medicinal plant use in Santiago Camotlán, Sierra Norte of Oaxaca, with a mainly Zapotec population. In a first stage, we interviewed specialists in depth and collected and identified plants for a catalogue of the medicinal plant flora (90 species). With this catalogue, we then interviewed a sample of the general population and the specialists on knowledge and frequency of use. The relationship between the sociodemographic variables and knowledge was analyzed by multiple regression. To explore differences of knowledge within the population, we identified three groups with a two-step cluster analysis; the results were compared statistically with a Kruskal-Wallis non-parametric test and then a post hoc Dunn’s test to see if all the differences between groups were significant. Age and occupation explained 54% of the variation of knowledge. Medicinal plant knowledge in the region persists mainly because of the necessity to treat the diseases that the “doctor does not cure,” the culture-bound syndromes, and the most common ailments, malfunctions of the digestive system.