Abstract Pepino mosaic virus (PepMV) is a highly infectious potexvirus, which has presently become a major pathogen for tomato crops worldwide. Since there is no effective method control for PepMV, strict preventive hygienic measures and cross‐protection have been established. However, the use of mild isolates to protect against aggressive isolates provides opportunities for interaction with other microorganisms, which under certain conditions may worsen disease symptoms. Thus, alternative control methods are needed. In this study we aimed at the development of chemical control against PepMV based on the use of heterocyclic compounds including symmetrical 2,5‐disubstituted 1,3,4‐oxadiazoles, symmetrical 2,5‐disubstituted 1,3,4‐thiadiazole and dihydrotetrazine derivatives. Results showed that spray application of three 1,3,4‐oxadiazole derivatives (OH‐Oxa, CH 3 ‐Oxa, NO 2 ‐Oxa) and of the derivative of 1,3,4‐thiadiazole (OH‐Thia) resulted in reducing the main symptoms of PepMV in tomato leaves, conversely to the dihydrotetrazine carboxylic acid. Double‐antibody sandwich enzyme‐linked immunosorbent assay (DAS‐ELISA) revealed that PepMV was not detected from tomato plants pre‐treated with the derivatives conferring elevated protection. Moreover, the protective ability of OH‐Oxa, CH 3 ‐Oxa, NO 2 ‐Oxa and OH‐Thia was closely related to the enhancement of the activity of antioxidant enzymes upon infection with PepMV.