Herbicide safeners are chemical or biological compounds used to protect crop plants from herbicide-induced non-target injury. The first safeners compounds were developed in the 1970s. Although initially used only in certain cereal species, they are now widely applied to staple crops such as maize, wheat, barley, and rice, as well as oilseed crops such as sunflower, rapeseed, soybean, and cotton. The primary function of safeners is to reduce the toxic effects of herbicides by stimulating plant metabolic detoxification pathways. This article comprehensively reviews the historical development, chemical classification, mechanisms of action, molecular and microbial interactions, and field performance of safeners. Literature findings indicate that safeners play an important role in reducing oxidative stress, particularly by activating the glutathione S-transferase (GST) and cytochrome P450 (CYP) enzyme families. Furthermore, safener applications have been shown to regulate the expression of numerous detoxification and stress response genes in plants. When the effectiveness of safener-herbicide combinations was examined under field conditions, a 10–30% increase in yield along with a marked reduction in phytotoxicity. Microbial and biotechnological approaches represent a new era in safener research. Consequently, safeners are not only adjuvants that increase herbicide selectivity but also important tools for understanding plant stress physiology. However, more comprehensive evaluation of environmental safety, residue management, and biological interactions is needed. This article provides a foundation for future research into the ecological, molecular, and biotechnological roles of safeners within sustainable agricultural systems.