Population densities and freshwater resources are not evenly distributed worldwide. This has forced farmers to use wastewater for the irrigation of food crops. This practice presents both positive and negative effects with respect to agricultural use, as well as in the context of environmental contamination and toxicology. Although wastewater is an important source of essential nutrients for plants, many environmental, sanitary, and health risks are also associated with the use of wastewater for crop irrigation due to the presence of toxic contaminants and microbes. This review highlights the harmful and beneficial impacts of wastewater irrigation on the physical, biological, and chemical properties of soil (pH, cations and anions, organic matter, microbial activity). We delineate the potentially toxic element (PTEs) build up in the soil and, as such, their transfer into plants and humans. The possible human health risks associated with the use of untreated wastewater for crop irrigation are also predicted and discussed. We compare the current condition of wastewater reuse in agriculture and the associated environmental and health issues between developing and developed countries. In addition, some integrated sustainable solutions and future perspectives are also proposed, keeping in view the regional and global context, as well as the grounded reality of wastewater use for crop production, sanitary and planning issues, remedial techniques, awareness among civil society, and the role of the government and the relevant stakeholders.