Little is known about the ecology of critically important antibiotic resistance among opportunistic human pathogens (e.g. _Escherichia coli_) on South American farms. By studying 70 farms in central-eastern Argentina, we identified that third-generation cephalosporin resistance (3GC-R) in _E. coli_ was mediated by mechanisms seen more often in certain species (pigs or dairy cattle) and that 3GC-R pig E. coli were more likely to be co-resistant to florfenicol and amoxicillin/clavulanate. This suggests that on-farm antibiotic usage is key to selecting the types of _E. coli_ present on these farms. 3GC-R E. coli were highly phylogenetically variable and we identified the de novo mobilisation of the resistance gene blaROB, alongside a novel florfenicol resistance gene, from pig pathogens into _E. coli_ on a mobile genetic element that was widespread in the study region. Overall, this shows the importance of surveying poorly studied regions for critically important antibiotic resistance which might impact human health.