The phytotoxicity of herbicides on crops is a major dilemma in agricultural production. Fortunately, the emergence of herbicide safeners is an excellent solution to this challenge, selectively enhancing the performance of herbicides in controlling weeds while reducing the phytotoxicity to crops. But owing to their potential toxicity, only a tiny proportion of safeners are commercially available. Natural products as safeners have been extensively explored, which are generally safe to mammals and cause little pollution to the environment. They are typically endogenous signal molecules or phytohormones, which are generally difficult to extract and synthesize, and exhibit relatively lower activity than commercial products. Therefore, it is necessary to adopt rational design approaches to modify the structure of natural safeners. This paper reviews the application, safener effects, structural characteristics, and modifications of natural safeners and provides insights on the discovery of natural products as potential safeners in the future.