Self-medication, as a form of self-care, is a common practice worldwide, and often involves the use of both over-the-counter and prescription-only medicines, including antibiotics, anti-malarials and others. Increasing concerns over the global emergence and spread of antimicrobial resistance point to the need to reduce and optimise the use of antimicrobial medicines, both in human and animal health. Over the past few decades, numerous studies on self-medication with antibiotics have sought to determine the prevalence, risks and/or factors related to ‘inappropriate’ use in different parts of the world. Yet much of this literature tends to follow a rather normative approach, which regards such practices as problematic and often irrational, frequently overlooking structural aspects, situated circumstances and individuals’ own reasoning. Based on a mixed methods social science research project in Maputo, which included a household survey, observations in pharmacies and interviews with users and healthcare providers, this paper aims to discuss self-medication in light of local users’ everyday practical reasoning. While situating self-medication within local contextual contingencies, the analysis highlights the ways in which personal and socially shared experiences, articulated with forms of knowledge and information provided by different sources, shape and inform practices of and attitudes towards self-medication with antibiotics. By looking at self-medication beyond (non-)prescription use, and by examining individuals’ decisions within their socioeconomic and therapeutic landscapes in Maputo, this study sheds light on the structural and relational factors that contribute to certain consumption practices that do not always follow biomedical recommendations of ‘rational’ or ‘appropriate’ use, helping to deconstruct and further problematise the various legitimate meanings and understandings of ‘responsible’ use.