A research was conducted at Nuclear Institute for Agriculture and Biology (NIAB), Faisalabad, Pakistan for the control of Cucumber mosaic virus in tomato. Aim of the study was to investigate the role of safe chemicals on disease control and molecular host-pathogen interaction. Safe chemicals included BTH (50mg/Litre) and Salicylic acid (SA) (1.4mg/liter) applied alone and in combination. During the first year of study, tomato plants were sown within glass house in the insect free environment and artificially inoculated with CMV. Next year, the experiment was conducted in the tunnel and plants were naturally inoculated by aphids with CMV which were found abundant during the cropping season. One month old healthy tomato nursery plants were transplanted after 1 hour root dip into the solutions of the SA and BTH. Later, BTH and SA were exogenously applied either weekly (w) or once (1) during the whole cropping season. Second objective of the study was to determine the role of BTH and SA for the induction of physical and biochemical changes in tomato under CMV stress condition. Experiments were conducted under completely Randomized design (CRD) with 5 replicates in glass house and RCBD in tunnel with three replicates. Means were compared with Tukey’s HSD test at 5% level of significance. Results from glass house experiment indicated that CMV severity index (out of 4.0) was least with the application of B-w (0.86), followed by BSA-1 (0.86), B1 (0.93) and BSA-w (1.26). Overall disease control was achieved up to 58-61%. Fruit quality parameters such as No. of fruits (30 No.) and fruit weight (558 g) were improved in the combined application of BTH and SA (BSA1). However, application of BTH alone enhanced the stress on tomato plants and resulted in minimum no. of fruits and plant height. Plant height was increased significantly in SA-w (36.66cm). Among biochemical parameters from leaf samples the Pigments (Lycopene, total carotenoids and chlorophyll) did not altered significantly. While defence related antioxidants/bioactive compounds were significantly elicited with both BTH and SA. Peroxidase (POD) activity was enhanced in weekly spray of BTH+SA. But it was more in ripened tomato fruit from SA and BTH treatments applied once in the season. Ascorbate peroxidase (APX) activity was higher after single dose of BTH. But tomato fruit showed more APX in weekly applied BTH. While Superoxide dismutase (SOD) was elevated in the SA treatments both in leaf and fruit samples. Malondialdehydes (MDA) concentration was more in weekly dose of BTH and BTH+SA combined. Tomato fruit also exhibited higher MDA contents in BTH+SA weekly treatment. Catalase (CAT) activity was accelerated after weekly dose of BTH+SA, however fruit indicated more CAT after single dose of BTH. Total Phenolic compounds (TPC) were higher in BTH treated samples and total soluble proteins also rose in weekly treatment of BTH and BTH+SA. Tunnel experiment demonstrated that CMV infection was least where BTH and SA were applied in combination. These doses were also helpful to retain the optimum yield. Additionally combined use of BTH & SA reduced aphid population during the experiment. Phytochemicals like Total proteins and Phenolics increased after single dose of BTH. However, POD was accelerated after combined dose of BTH & SA. Protease, MDA and SOD were raised after weekly dose of BTH and single spray of BTH+SA. While CAT and APX activity was elevated by weekly dose of BTH+SA. Activity of pigments was shifted with little margins in the tunnel experiment. Overall conclusion can be drawn that, combine application of BTH and SA gave better protection to tomato against CMV and provided efficient vector control. This protection was accompanied by various physico-chemical alterations with promising benefits for defence activity in host plants.