This article introduces and analyzes some of the central elements of the theoretical, ethical, and political works of the Portuguese sociologist Boaventura de Sousa Santos. Using his seminal work Epistemologies of the South, we aim to create a dialogue with the Chicana critic Gloria Anzaldúa’s theoretical framework as initially developed in her book Borderlands/La Frontera: The New Mestiza. Both De Sousa Santos and Anzaldúa, within the context of a critical decolonial approach, elaborated their respective theories compelled by the need to move away from modern paradigms and consequently acknowledge the paradigmatic condition of postmodernity. We have a particular interest in exploring deeply the proposal of both theorists in their creation of what De Sousa Santos came to name the ‘hermeneutics of suspicion.’ This positions itself against the Modern totalizing knowledges and universalisms and as a way to escape the Eurocentric mono-culturalist monologue and thereby produce an ‘ecology of knowledge’ as a counter-epistemology. From a moderate anti-essentialist strategic position, the work of both De Sousa Santos and Anzaldúa strongly emphasizes the role of lived experience, the knowledge of indigenous peoples, and the use of hybridity/mestizaje as a way to claim knowledge and give a voice to the group that is violently silenced and excluded. Lastly, it is our intention in this paper to offer an introduction to some key points within the wide theoretical production of the critical decolonial sociologist Boaventura De Sousa Santos.