Although antibiotics are beneficial for treating infections, their release into the environment has raised global concerns. In this work, the interactions of cellulose nanocrystal (CNC) derivatives with sulfamethoxazole (SMX), ciprofloxacin (CIP), and doxycycline (DOX) antibiotics were studied fundamentally. CNC was carboxyalkylated to bear different carbon chain lengths but similar negative charges on its surface. The highest level of adsorption of DOX on the carboxypantadecanated CNC (i.e., carboxyalkylated CNC with more carbon spacer, PCNC) occurred at pH 6.0, which was due to the electrostatic and π interactions along with hydrogen bonding. The contact angle and quartz crystal microbalance (QCM) adsorption analyses revealed a faster interaction and adsorption of DOX than other antibiotics on PCNC. The results also depicted the diffusion of DOX into the porous structure of CNC derivatives, especially that of PCNC. Also, a more compact adsorbed layer of DOX was formed on PCNC than on other CNC derivatives. Carboxyalkylation was observed to slightly reduce the surface area of CNC, while the antibiotic adsorption drastically increased the surface area of CNC due to their adsorption on the surface. XPS analysis revealed that carboxyalkylation significantly enhanced the