In Mexico, there is a lengthy tradition, dating back at least to Spain’s colonial occupation, of rendering Indigenous-speaking peoples and Afro-Mexican peoples as inferior. During the 500 years after the Spanish invasion, Indigenous and Afro-Mexican peoples in the Americas, however, have taken colonial ideals as practices to be resisted. This resistance has occurred throughout Central and South America. Focusing on Mexico, the purpose of this presentation is to show how Indigenous and Afro-Mexican actors have challenged coloniality that attempts to render them as “primitive” and “backward”. First, I present how Indigenous peoples repositioned themselves as multilingual and multiliterate individuals at the onset of colonial times in the 16th century. Second, fast-forwarding 500 years to the present, I present how Indigenous and Afro-Mexican peoples in Oaxaca—the most culturally and linguistically diverse state of Mexico and home to 16 different Indigenous ethnic and Afro-Mexican groups—are at the present time resisting coloniality by working collaboratively in cooperatives and colectivos that use multilingual and multiliteracies practices in order to reposition themselves in the world. Finally, I discuss the onto-epistemological perspectives of three Ayuk speakers (an Indigenous language in Mexico) by presenting and then analyzing their life stories in connection to their “customs” that challenge binaries and go beyond humanism. To conclude I argue that we have much to learn from Indigenous and Afro peoples who have challenged colonialism and coloniality for centuries.