Low surface energy substrates, which include many plastics and polymers, present challenges toward achieving uniform, adherent coatings, thus limiting intended coating function. These inert materials are common in various applications due to favorable bulk, despite suboptimal surface, properties. The ability to functionally coat low surface energy substrates holds broad value for uses across medicine and industry. Cyclodextrin-based materials represent an emerging, widely useful class of coatings, which have previously been explored for numerous purposes involving sustained release, enhanced sorption, and reversible reuse thereof. In this study, substrate exposure to nonthermal plasma was explored as a novel means to improve uniformity and adherence of cyclodextrin-based polyurethane coatings upon unreceptive polypropylene substrates. Plasma effects on substrates were investigated using contact angle goniometry and X-ray photoelectron spectroscopy (XPS). Plasma impact on coating uniformity was assessed through visualization directly and microscopically. Plasma effects on coating adhesion and bonding were studied with mechanical lap-shear testing and XPS, respectively. Substrate surface wettability and oxygen content increased with plasma exposure, and these modifications were associated with improved coating uniformity, adhesion, and interfacial covalent bonding. Findings demonstrate utility of, and elucidate mechanisms behind, plasma-based surface activation for improving coating uniformity, adherence, and performance on inert polymeric substrates.