BACKGROUND Cucumber downy mildew (CDM) is a severe plant disease and affects the yield of cucumber production worldwide. As the resistance toward conventional fungicides is emerging as a ubiquitous issue, it is urgent to discover efficient fungicides with unique structures. RESULTS In this study, a series of novel phenylpyridine derivatives were designed and synthesized. Bioassays revealed that most of these compounds possessed excellent fungicidal activities against CDM. Among the phenylpyridine compounds, 2‐(4‐(4‐(tert‐butyl)benzyl)piperazin‐1‐yl)‐6‐phenylnicotinonitrile (C8) [half‐maximal effective concentration (EC50) = 4.40 mg L−1] displayed the highest activity, which was better than those of the commercial fungicides, such as azoxystrobin (EC50 = 42.77 mg L−1) and flumorph (EC50 = 41.94 mg L−1). Furthermore, the molecular electrostatic potential of high‐activity compound C8 indicated that nitrogen atom of the cyano group on the pyridine ring was in the negative region and may easily form hydrogen bonds and allow for electrostatic interactions with potential receptors. CONCLUSIONS This study demonstrated that the novel N‐substituted piperazine‐containing phenylpyridine derivatives could be further developed as a candidate compound to control CDM.