To discover bioactive natural products from mangrove sediment-derived microbes, a chemical investigation of the two Beibu Gulf-derived fungi strains,Talaromycessp. SCSIO 41050 andPenicilliumsp. SCSIO 41411, led to the isolation of 23 natural products. Five of them were identified as new ones, including two polyketide derivatives with unusual acid anhydride moieties named cordyanhydride A ethyl ester (1) and maleicanhydridane (4), and three hydroxyphenylacetic acid derivatives named stachylines H–J (10–12). Their structures were determined by detailed nuclear magnetic resonance (NMR) and mass spectroscopic (MS) analyses, while the absolute configurations were established by theoretical electronic circular dichroism (ECD) calculation. A variety of bioactive screens revealed three polyketide derivatives (1–3) with obvious antifungal activities, and4displayed moderate cytotoxicity against cell lines A549 and WPMY-1. Compounds1and6at 10 μM exhibited obvious inhibition against phosphodiesterase 4 (PDE4) with inhibitory ratios of 49.7% and 39.6%, respectively, while5,10, and11showed the potential of inhibiting acetylcholinesterase (AChE) by an enzyme activity test, as well as in silico docking analysis.