The antimicrobial agents counter with multidrug resistant (MDR) pathogenic microbes, compounded with the raised number of patients, are of great concern all around the world, which has given impetus to the research on less explored eco-friendly agents such as endophytes which have emerged as a source of novel drugs. Endophytes residing in plants produce natural compounds of therapeutic importance which can find a way in pharmaceutical industry. The endophytic actinomycetes isolated from Panxi plateau and endophytic Streptomyces sp. TQR12-4 isolated from Elite Citrus nobilis fruit shows large spectrum antimicrobial activity inhibiting pathogens like Colletotrichum truncatum, Geotrichum candidum, Fusarium. oxysporum, and F. udum. Endophytic strains of Bacillus sp. isolated from Adhatoda beddomei and Garcinia xanthochymus synthesized silver nanoparticles (AgNPs) have promising antimicrobial potential. With potent drug possibilities, structural varieties of bioactive metabolites such as peptides, alkaloids, isocoumarins, steroids, quinines, terpenoids, phenols, perylene derivatives, and flavonoids have triggered large interest in characterization and isolation of eco-friendly endophytes, challenging the pathogenicity of MDR microbes. Endophytes have impacted our lives in several ways and exploiting them as a novel source of bioactive metabolites against MDR microbes is the priority endeavor of this chapter. © 2023 Elsevier Inc. All rights reserved.