Herbicide safeners are agricultural chemicals that protect crops from herbicide injury and improve the safety of herbicides and the effectiveness of weed control. Safeners induce and enhance the tolerance of crops to herbicides through the synergism of multiple mechanisms. The principal mechanism is that the metabolic rate of the herbicide in the crop is accelerated by safeners, resulting in the damaging concentration at the site of action being reduced. We focused on discussing and summarizing the multiple mechanisms of safeners to protect crops in this review. It is also emphasized how safeners alleviate herbicide phytotoxicity to crops by regulating the detoxification process and conducting perspectives on future research on the action mechanism of safeners at the molecular level.