Agriculture is one of the most critical domains of healthy living and a basic need of many agro-product-based countries’ economic upliftment. With the increasing problems of global warming, anthropogenic interference, and the introduction of high-yielding varieties, and application of chemical fertilizers–pesticides/weedicides, agricultural productivity is backfiring, and the biotic stress caused by pathogenic fungi and bacteria is going logarithmic. Bio-based novel solutions are highly solicited to reduce the events of agricultural catastrophes, and biocontrol agent/microbe-mediated options are the safest ones to go for. Soil fungi or actinobacteria and their endophytic counterparts can sometimes favor plant growth and provide a strong defense against plant pathogens. Actinobacteria or ray fungi are one step ahead in this respect due to their unique production abilities of diverse antibiotics and high guanine and cytosine contents in their core genome. They are an integral part of the plant–rhizospheric microbiome and are critical in plant growth and protection from biotic and abiotic stress. Thus, they contribute to developing sustainable agricultural practices and act as a biocontrol agent to tackle devastating phytopathogens. Their synthesized exo-metabolomes, exopolysaccharides, or low-molecular-weight volatile and nonvolatile secondary metabolites are effective and perform different plant growth-promoting attributes. Also, the direct introduction of actinobacterial consortium or synthetic communities are practical plant nurturers. The chapter focuses on novel actinobacterial isolates from rhizospheric and endophytic origin, along with their utility as plant-protecting agents against detrimental phytopathogens.