Late wilt disease, caused by the fungus M. maydis, threatens commercial maize production in high-risk areas. Thus, the search for control options against the pathogen is one of the top priorities in Israel, Egypt, and other countries. Disease-resistant maize genotypes can reduce the damages. Yet, aggressive variants of the fungus can overcome host resistance. The current study aimed at inspecting Trichoderma asperellum and its secreted metabolite, 6-pentyl-α-pyrone (6-PP), against the pathogen in plants over a full growth period. First, adding T. asperellum directly to seeds with sowing provides significant protection to sprouts (up to 42 days) in a growth room, with more than two-fold growth promotion and reduced pathogen root infection (detected by real-time PCR). The same procedure applied in a commercial field was less beneficial in rescuing the plants’ growth and yield. Still, it reduced the cobs’ symptoms by 11% and resulted in nine-fold lower levels of the pathogen’s DNA in the stem tissue. Second, the T. asperellum purified 6-PP compound (30 µg/seed) was used in seed coating and tested against the T. asperellum secretory metabolites’ crude (diluted to 50%). At the season’s end, these treatments improved plant biomass by 90–120% and cob weight by 60%. Moreover, the treatments significantly (p < 0.05) reduced the symptoms (up to 20%) and pathogen infection (94–98%). The current study’s results reveal the potential of 6-PP as a new fungicide against M. maydis. Such a treatment may protect maize plants from other soil diseases.