Per- and polyfluoroalkyl substances (PFAS) are highly persistent synthetic organic contaminants that can cause serious human health concerns such as obesity, liver damage, kidney cancer, hypertension, immunotoxicity and other human health issues. Integrated crop-livestock systems combine agricultural crop production with milk and/or meat production and processing. Key sources of PFAS in these systems include firefighting foams near military bases, wastewater sludge and industrial discharge. Per- and polyfluoroalkyl substances regularly move from soils to nearby surface water and/or groundwater because of their high mobility and persistence. Irrigating crops or managing livestock for milk and meat production using adjacent waters can be detrimental to human health. The presence of PFAS in both groundwater and milk have been reported in dairy production states (e.g., Wisconsin and New Mexico) across the United States. Although there is a limit of 70 parts per trillion of PFAS in drinking water by the U.S. EPA, there are not yet regional screening guidelines for conducting risk assessments of livestock watering as well as the soil and plant matrix. This systematic review includes (i) the sources, impacts and challenges of PFAS in integrated crop-livestock systems, (ii) safety measures and protocols for sampling soil, water and plants for determining PFAS concentration in exposed integrated crop-livestock systems and (iii) the assessment, measurement and evaluation of human health risks related to PFAS exposure.