A chemical investigation into fermentation product of Talaromyces sp. KYS-41, a fungus isolated from Kunyu Mountain soil, resulted in the discovery and identification of 27 polyketides. Notably, talaromyketides A-I (1-9) are reported for the first time, with talaromyketides A-C (1-3) being three pair of enantiomers. Talaromyketides A-D (1-4) display novel frameworks and are regarded as products resulting from oxidative ring-opening and/or subsequent rearrangement of the bibenzyl derivatives. Talaromyketide A (1) exhibits a scaffold comprising an isochroman-1,4-dione, whereas talaromyketide B (2) showcases the structural backbone of a naphthalen-1(4H)-one. Talaromyketides C (3) and D (4) are the outcomes of oxidative ring-opening of one of the phenyl rings in bibenzyl derivatives. Biological evaluations demonstrated that compounds 2b, 9, and 18-21 show significant anti-inflammatory activity with IC