Poultry litter is a valuable source of nutrients for crop production, but its use in agriculture can lead to environmental and public health concerns due to the presence of pollutants, antibiotic-resistant bacteria (ARB) and antibiotic-resistant genes (ARGs). We compared the effect of different on-farm poultry litter composting processes on physicochemical, biological, and toxicological parameters, as well as on the occurrence of antibiotics and resistant Escherichia coli. The composting treatments consisted of passively-aerated piles C:N = 19 (PAC₁₉), mechanically-aerated piles C:N = 19 (MAC₁₉), and mechanically-aerated piles C:N = 30 (MAC₃₀). Poultry litter composting led to a significant reduction of antibiotic residues, enteroparasites and antibiotic resistant E. coli. The conditions of the process, such as extra C source and mechanical aeration influence the quality of the final product. MAC₁₉ is a low-cost effective method to reduce the potential risks associated with poultry litter use in agriculture and produce good quality compost.