Certain microbial agent is widely used for the biocontrol of particular species of organism that are mostly dependent on space and resource competition. A large number of bioactive compounds provided through microbial metabolism produced by different microbes, i.e. fungi, viruses, nematodes, bacteria and other insects, are significantly used for the control of many plant diseases. Endophytes exist inside the plant system in the form of fungal and bacterial microorganism, having a positive association with its host. Phyto-endophytes produce a variety of volatile organic compounds (VOCs) forming a symbiotic relationship with their host under a very high competitive environment. Endophytes produce a diverse group of secondary metabolites, i.e. phenolic compounds, alkaloids, steroids, tannins, quinones, terpenoids and saponins which have challengeable antimicrobial, anti-insect and anticancer properties against different host infections. They live asymptomatically in the cellular environment inside plants, performing different functions, like molecules of signalling in response to different stimuli for survival mutually and secondary metabolite production. Where they stimulate various immune responses against biotic and abiotic stresses excluded phytopathogens by niche competition. In fact, metabolomic studies have demonstrated that endophyte genes associated to specific metabolites are involved in plant growth promotion (PGP) by stimulating plant hormone production such as auxins and gibberellins or as plant protective agents against microbial pathogens, cancer, and insect pests, but ecofriendly and eco-safe. Crop performance could be improved by using biocontrol mechanism under salinity stress in the development of agricultural applications. This chapter aims with the comprehensive uses and contribution of endophytic microbes especially bacteria and fungi as an impending source of biocontrol and plant growth-promoting activities.