Sweet pepper (Capsicum annuum L.) is one of the most widely produced vegetable plants in the world. Fusarium wilt of pepper is one of the most dangerous soil-borne fungal diseases worldwide. Herein, we investigated the antifungal activities and the potential application of two chalcone derivatives against the phytopathogenic fungus, Fusarium equiseti, the causal agent of Fusarium wilt disease in vitro and in vivo. The tested compounds included 3-(4-dimethyl amino-phenyl)-1-{6-[3-(4 dimethyl amino-phenyl)-a cryloyl]-pyridin-2-yl}-propanone (DMAPAPP) and its metal complex with ruthenium III (Ru-DMAPAPP). Both compounds had potent fungistatic activity against F. equiseti and considerably decreased disease progression. The tested compounds enhanced the vegetative growth of pepper plants, indicating there was no phytotoxicity on pepper plants in greenhouse conditions. DMAPAPP and Ru-DMAPAPP also activated antioxidant defense mechanisms that are enzymatic, including peroxidase, polyphenole oxidase, and catalase, and non-enzymatic, such as total soluble phenolics and total soluble flavonoids. DMAPAPP and Ru-DMAPAPP also promoted the overexpression of CaCu-SOD and CaAPX genes. However, CaGR and CaMDHAR were downregulated. These results demonstrate how DMAPAPP and Ru-DMAPAPP could be employed as a long-term alternative control approach for Fusarium wilt disease as well as the physiological and biochemical mechanisms that protect plants.