Exposure to antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) from natural and agricultural ecosystems such as soil can significantly affect the dissemination of resistance determinants to the human microbiome. Soil contains a diverse natural resistome and also serves as an important environmental reservoir for ARB and ARGs derived from water sources, aerosols, and sewage sludge. Soil microbiomes have been impacted worldwide by the use and overuse of antibiotics for anthropogenic activities (clinical use and livestock production) and agricultural practices (manure application and irrigation with wastewater). The dynamics and persistence of ARB and ARGs in soil are affected by soil management and environmental factors. Both abiotic and biotic factors (pH, temperature, organic matter, nutrient availability, and syntrophic, competing or antagonistic organisms) can act as driving forces for ARG fate, evolution, and horizontal gene transfer processes. Meanwhile, ARGs in soil may also be transferred to other environments, such as groundwater and the phytosphere. To tackle the potential threat of ARGs, treatment measures (aerobic composting, anaerobic digestion, and disinfection) have been evaluated to reduce the selective pressure and import of ARGs into soil. Furthermore, the “One Health” approach was put forward to manage the development and dissemination of ARGs in a cross-disciplinary manner, to more holistically reduce human risk to the lowest level.