Due to the exceptional topographical situations, Mariana trench’s sediment can be a unique habitat for deep-sea microorganisms with the talent to produce structurally differentiated secondary metabolites. It leads to the production of new novel bioactive metabolites for drug discovery. This review mainly provides on the summary of secondary metabolites with biological activities isolated from deep-sea fungi and bacteria in the Mariana trench sediments during 2010-2021. Effective technical route and experimental plan for screening and obtaining natural active compounds from deep sea microorganisms are also summarized in this review. Mariana trench can be regarded as a source of unexplored and new chemical diversity for drug discovery because numerous new novel compounds have been discovered by researchers within only a few studies. The number of twenty-nine new secondary metabolites have been discovered from microorganisms in Mariana trench’s sediment. Among them, fourteen new phenazine compounds are isolated from Dermacoccus abyssi sp. nov., strains MT1.1 and MT1.2 14,27,31-32 and four new tetramic acids from Cladosporium sphaerospermum L3P3 26, one new meroterpenoid from penicillium sp. SY2107 22, three new pyrrole alkaloids from Bacillus subtilis SY2101 23, one new novel salicylamide analogue, two new diketopiperazine derivatives, one new phenylethanediol from Streptomyces sp. SY1965 21, three new polyketides from Phoma sp 30, respectively.