The discovery of antimicrobial agents for treatment of diseases in humans, animals and plants was one of the most significant events of the 20th century. Notwithstanding their importance, acquired resistance has become increasingly evident and this pattern has followed the introduction of each new antimicrobial agent. Antimicrobial resistance (AMR) has not only led to unwarranted mortality rates in humans, but also presents a major economic burden to farmers, governments and the rest of society. Hence, the alarming worldwide escalation of AMR poses a serious threat to public health, agricultural production and food security, and can cause major disruption globally. Whilst there has been progress in understanding the causes of AMR, there is a dearth of knowledge on how to empirically mitigate it using the One Health approach in low resource settings. Furthermore, the occurrence of AMR in the Pacific region is poorly understood. Using Fiji as a case study and through the Enhancing the Management of Antimicrobial Resistance (EMAR) project, we illustrate how systems thinking can be applied in the context of AMR. We also describe the impact of AMR on agricultural systems, and demonstrate how we are tackling the problem of resistance in Fiji to improve health, agricultural production, and ecosystem outcomes in a sustainable and cost-effective manner. We envisage that the approach used in Fiji, including the lessons learnt, will be scaled out to other low resource settings to reduce the spread of AMR.