Charcoal rot disease (CRD), caused by the phytopathogenic fungus Macrophomina phaseolina, is a significant threat to cotton production in Israel and worldwide. The pathogen secretes toxins and degrading enzymes that disrupt the water and nutrient uptake, leading to death at the late stages of growth. While many control strategies were tested over the years to reduce CRD impact, reaching that goal remains a significant challenge. The current study aimed to establish, improve, and deepen our understanding of a new approach combining biological agents and chemical pesticides. Such intervention relies on reducing fungicides while providing stability and a head start to eco-friendly bio-protective Trichoderma species. The research design included sprouts in a growth room and commercial field plants receiving the same treatments. Under a controlled environment, comparing the bio-based coating treatments with their corresponding chemical coating partners resulted in similar outcomes in most measures. At 52 days, these practices gained up to 38% and 45% higher root and shoot weight and up to 78% decreased pathogen root infection (tracked by Real-Time PCR), compared to non-infected control plants. Yet, in the shoot weight assessment (day 29 post-sowing), the treatment with only biological seed coating outperformed (p < 0.05) all other biological-based treatments and all Azoxystrobin-based irrigation treatments. In contrast, adverse effects are observed in the chemical seed coating group, particularly in above ground plant parts, which are attributable to the addition of Azoxystrobin irrigation. In the field, the biological treatments had the same impact as the chemical intervention, increasing the cotton plants' yield (up to 17%), improving the health (up to 27%) and reducing M. phaseolina DNA in the roots (up to 37%). When considering all treatments within each approach, a significant benefit to plant health was observed with the bio-chemo integrated management compared to using only chemical interventions. Specific integrated treatments have shown potential in reducing CRD symptoms, such as applying bio-coating and sprinkling Azoxystrobin during sowing. Aerial remote sensing based on high-resolution visible-channel (RGB), green-red vegetation index (GRVI), and thermal imaging supported the above findings and proved its value for studying CRD control management. This research validates the combined biological and chemical intervention potential to shield cotton crops from CRD.