Periodontal diseases are inflammatory diseases triggered by pathogenic oral bacterial species, such as <i>Porphyromonas gingivalis</i>. Zafirlukast (ZAF) has displayed antibacterial activity against <i>P. gingivalis</i>. Herein, we report the design, synthesis, and selective antibacterial activity of 14 novel third-generation ZAF derivatives. Two second-generation ZAF derivatives were tested as they were not previously tested against <i>P. gingivalis</i> ATCC 33277. Most third-generation derivatives displayed superior/selective antibacterial activity against <i>P. gingivalis</i> compared to ZAF and its second-generation derivatives. The compounds displayed bactericidal activity against <i>P. gingivalis</i>, inhibited biofilm growth, displayed no hemolytic activity, and displayed less cytotoxicity against mammalian cells than ZAF. The superior/selective antibacterial activity of ZAF derivatives against <i>P. gingivalis</i>, increased safety profile, and inhibition of biofilm growth compared to ZAF indicate that the compounds, especially <b>21a</b>, <b>21b</b>, and <b>24g</b>, show promise as antibacterial agents for future studies to test their potential for preventing and treating <i>P. gingivalis</i>-induced periodontal diseases.