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Fungal diseases have always been a major problem for cantaloupe crops; however, synthetic fungicides are hazardous to humans and the environment. Consequently, a feasible alternative to fungicides without side effects could be by using bio agents and naturally occurring plants with antibacterial potential. This study has achieved a novel procedure for managing wilt and root rot diseases by potentially using <i>Trichoderma</i> sp. culture filtrates in consortium with plant extract of <i>Calotropis procera</i>, <i>Rhizoctonia solani</i>, <i>Fusarium oxysporum</i>, and <i>Pythium ultimum</i>, which were isolated from infected cantaloupe roots with identified root rot symptoms. The antagonistic activity of four <i>Trichoderma</i> isolates and analysis of antibiotics and filtrate enzymes of the most active <i>Trichoderma</i> isolate were determined as well as phytochemical analysis of <i>C. procera</i> plant extract using HPLC-UV. The obtained results showed that all <i>Trichoderma</i> isolates considerably lowered the radial growth of <i>P. ultimum</i>, <i>R. solani</i>, and <i>F. oxysporum</i> in varying degrees. The scanning electron micrographs illustrate the mycoparasitic nature of <i>Trichoderma</i> sp. on <i>F. oxysporum</i>. The phytochemical analysis of <i>C. procera</i> indicated that phenolic contents were the major compounds found in extracts, such as vanillin (46.79%), chlorogenic acid (30.24%), gallic acid (8.06%), and daidzein (3.45%) but including only a low amount of the flavonoid compounds rutin, naringenin, and hesperetin. The Pot experiment’s findings showed that cantaloupe was best protected against wilting and root rot diseases when it was treated with both <i>Trichoderma</i> sp. culture filtrates (10%) and <i>C. procera</i> extract of (15 mg/mL), both alone and in combination. This study demonstrates that the application of bio agent <i>Trichoderma</i> spp. filtrate with <i>C. procera phenol</i> extract appears useful for controlling wilting and root rot disease in cantaloupe. This innovative approach could be used as an alternative to chemical fungicide for the control of wilting and rot root diseases.