The surface compatibility and antibacterial properties of biomaterials are crucial to tissue engineering and other medical applications, and plasma-assisted technologies have been employed to enhance these characteristics with good success. Herein, we describe and review the recent developments made by our interdisciplinary team on self-antimicrobial biomaterials with emphasis on plasma-based surface modification. Our results indicate that a self-antibacterial surface can be produced on various types of materials including polymers, metals, and ceramics by plasma treatment. Surface characteristics such as roughness, microstructure, chemistry, electronegativity, free energy, hydrophilicity, and interfacial physiochemistry are important factors and can be tailored by using the appropriate plasma-assisted processing parameters. In particular, mechanistic studies reveal that the interfacial physiochemical processes, biocidal agents, and surface free energy are predominantly responsible for the antibacterial effects of plasma-modified biomaterials.