The synergistic interaction between mesotrione, a hydroxyphenylpyruvate dioxygenase (HPPD)-inhibiting herbicide, and atrazine, a photosystem II (PS II)-inhibiting herbicide, has been identified in the control of several weed species. A series of dose–response studies examined the synergistic effect of these herbicides on a susceptible (S) wild radish population. The potential for this interaction to overcome target-site psbA gene-based atrazine resistance in a resistant (R) wild radish population was also investigated. Control of S wild radish with atrazine was enhanced by up to 40% when low rates (1.0 to 1.5 g ha−1) of mesotrione were applied in combination. This synergistic response was demonstrated across a range of atrazine–mesotrione rate combinations on this S wild radish population. Further, the efficacy of 1.5 g ha−1 mesotrione increased control of the R population by a further 60% when applied in combination with 400 g ha−1 of atrazine. This result clearly demonstrated the synergistic interaction of these herbicides in overcoming the target-site resistance mechanism. The mechanism responsible for the observed synergistic interaction between mesotrione and atrazine remains unknown. However, it is speculated that an alternate atrazine binding site may be responsible. Regardless of the biochemical nature of this interaction, evidence from whole-plant bioassays clearly demonstrated that synergistic herbicide combinations improve herbicide efficiency, with lower application rates required to control weed populations. This, combined with the potential to overcome psbA gene-based triazine resistance, and, thereby, regain the use of these herbicides, will result in more sustainable herbicide use.