Plants are a major source of natural bioactive compounds which have been exploited from time immemorial by our ancestors and have been used as a potent therapy for curing diverse diseases. Endophytic microorganisms exist in a symbiotic relationship with the host plants, residing in its health tissues, producing different compounds with potent pharmacological and therapeutic potential. Interestingly, endophytes produce secondary metabolites and are a major source of natural bioactive compounds. The increasingly prevalence of antimicrobial resistance makes natural bioactive compounds to be highly sought after, making endophytes an untapped source of potent therapeutic compounds. These bioactive compounds from endophytes possess antimicrobial, immunosuppressive and anti-inflammatory properties, making them highly valuable bioactive compounds. The biodiversity of these endophytic microorganisms makes them unique and a highly untapped source of bioactive compounds necessitating their bioprospecting for these novel bioactive compounds. This entails the isolation of these endophytes using culture medium, recovering and purifying bioactive compounds from the isolated cultures and subsequently screening the purified bioactive compounds for its antimicrobial activities. Additionally, these endophytes can be bioengineered, with the gene responsible for the production of these pharmacologically bioactive compounds further amplified, enhancing its syntheses. This is particularly important especially as most pathogenic microorganisms are becoming resistant to available drugs. Thus, the bioprospecting of microbial endophytes is necessary for the development of novel drugs which are effective against pathogenic microorganisms.