Organoclays were prepared by means of cation-exchange reactions using different concentrations of chlorhexidine diacetate and two different types of clays: montmorillonite and palygorskite. The antibacterial activity against Escherichia coli was evaluated by means of disk diffusion tests as well as through bacterial growth inhibition (monitored by optical density measurements) in Luria broth media. Results indicate that modified palygorskites showed a greater antibacterial activity than those exhibited by modified montmorillonite, as latter only displayed antibacterial properties at the highest chlorhexidine diacetate loading. Modeling of chlorhexidine release was also performed and the models best described the drug release phenomena depended on the type of clay; being the Higuchi model and Korsemeyer–Peppas model for montmorillonite, whereas the zero-order model and Korsemeyer–Peppas model for palygorskite.