Abstract Type III secretion systems (T3SS) are syringe-like apparatuses acting as protein transport nanomachines found in most Gram-negative bacterial pathogens. They can inject effector proteins into the host cell cytoplasm, crossing the host cell membrane, and cause infection. Due to their critical role in pathogenicity, T3SS represent attractive targets for vaccinations and disease treatments. This review elucidates the overarching structural framework and operational mechanisms of T3SS apparatuses while also delineating the responsiveness of phytobacterial T3SS to host-derived signals and the nuanced orchestration of their activities by host and environmental stimuli. This discussion encompasses shared features and idiosyncratic attributes among a spectrum of pathogens, including but not limited to Pseudomonas syringae , Ralstonia , Xanthomonas , and Erwinia . Additionally, we scrutinize the contribution of natural products and synthetic chemicals as T3SS inhibitors, elucidating their hallmark and role in the ongoing quest for and design of novel drugs. An in-depth comprehension of T3SS functionality and the modes of action of diverse inhibitors holds promise for developing innovative drugs aimed at swiftly suppressing phyto-pathogenicity elicited by a spectrum of bacterial species.