Antimicrobial resistance (AMR) poses a significant global health threat, particularly in low- and middle-income countries (LMICs). Self-treatment with antibiotics, the practice of using antibiotics without professional guidance, is often considered an important contributor to the emergence and spread of AMR. This study investigated the drivers of self-treatment in three common types of agricultural communities in northern Tanzania. The research employed a comprehensive array of methods, including cross-sectional surveys (n = 790), interviews (n = 30) and observations (n = 178) targeting both antibiotic (human and animal) providers and users (patients and farmers). Qualitative interview data were analysed using a coding and association matrix, while descriptive analyses were performed on survey and observation data. Self-treatment with antibiotics was highly prevalent in all communities. Between 41.0% (self-reported) and 60.3% (observed) of human antibiotics were obtained without a prescription and we observed that veterinary antibiotics were regularly purchased in retail shops without referral by a professional. Structural deficiencies in the healthcare system drove this practice: limited access to healthcare facilities, medication stockouts and prolonged waiting times were identified as key factors. The absence of safety nets like insurance schemes further contributed to self-medication. Retail shops offered a convenient and cost-effective alternative when antibiotics were inaccessible or unaffordable. Notably, informal networks comprising treatment vendors, friends or neighbours, as well as personal experiences played a crucial role in guiding individuals in their self-treatment decisions by providing advice on treatment choice and modalities. Addressing self-treatment requires a multi-faceted approach. Improving the availability and accessibility of antibiotics, enhancing healthcare services and involving retail vendors in antibiotic stewardship are essential. Structural issues like access to diagnostics and medicines must be tackled, alongside reducing barriers and incentivising individuals to use professional healthcare services. Training retail vendors to sell specific first-line antibiotics over the counter with guidance on appropriate usage should be considered. Such bottom-up interventions will enable sustainable promotion of responsible antibiotic use, mitigating AMR emergence and securing a healthier future for all.