Peptidomimetics represent a promising class of biologically active compounds with broad therapeutic potential. In general, peptidomimetics mimic the functions of natural peptides in the human body while overcoming their inherent limitations (e.g., low stability or poor bioavailability), thus finding application in the treatment of a wide range of diseases. This study focuses on the synthesis and cytotoxic properties of short original ornithine-based peptidomimetics derived from substituted O-benzyl-protected salicylic acid (salicylamides), where L-ornithine is further modified with various aromatic amines, and on the evaluation of their biological activity against the A549 human lung carcinoma cell line. Salicylic acid–based peptidomimetics have previously been synthesized by our research group, demonstrating both anticancer and antimicrobial activity. Ornithine-containing peptidomimetics represent synthetic precursors leading to arginine-based peptidomimetics. Arginine peptidomimetics exhibit a broad spectrum of biological activities, including antimicrobial, antiviral, antifungal, anticancer (e.g., cilengitide), and activity against cardiovascular (e.g., argatroban) and neurodegenerative diseases. The A549 cell line is a standard in vitro model for testing novel candidate anticancer agents against non-small cell lung carcinoma (NSCLC), the most prevalent clinical form of lung cancer. In this study, short ornithine-derived and specific salicylamide derivatives with potential biological activity against the A549 cell line were prepared. The peptidomimetic backbone was synthesized via Steglich amidation, and the side chain was modified. The anticancer activity of the synthesized compounds was determined in vitro against the A549 cell line, for final compounds as well as for their precursors. The presentation will address the structure–activity relationships observed in this series.