Most rural households depend on agriculture for their livelihoods, and livestock are often an integral part of their production systems. Achieving food security in the face of population growth, climate change, resource degradation, water scarcity, poverty, food loss, and conflict requires a multidimensional approach. Reducing the pressure of food production on the environment while feeding an ever-growing human population is one of the greatest challenges facing humanity. Aquaculture in particular is increasingly seen as a critical source of food security, providing 70% of the world’s fish supply. Sustainability will be a key focus for aquaculture production in the future. There will be an increased emphasis on reducing environmental impacts, improving resource efficiency, and minimizing the use of antibiotics and chemicals. Unfortunately, this growth in aquaculture and the associated use of antibiotics has also brought with it a growing threat of antimicrobial resistance (AMR). Here, I try to unravel the drivers behind the rise of antibiotic resistance and the way forward to deal with the threat of antibiotic resistance, the role of environmental drivers in the rise of antibiotic resistance, and in particular the threat of antibiotic resistance in aquaculture as aquaculture is at the crossroads between global warming and antibiotic resistance. Beyond aquaculture, I also look at the threat of antibiotic resistance to the ecosystem with some perspectives on how to reduce the risks of antibiotic resistance. The complexity of managing and reducing the impact of the emergence of antibiotic-resistant bacteria on human, animal, and environmental health (OneHealth) is a major public health problem that requires urgent global action. The time to act is now, and we can be part of the solution.