Six new azaphilone derivatives, talaraculones A-F (1-6), together with five known analogues (7-11), were obtained from the saline soil-derived fungus Talaromyces aculeatus. The absolute configurations of 1 and 6 were assigned by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. Compounds 1 and 5 represent the first reported azaphilone derivatives with a C4 aliphatic side chain and a methylal group at C-3, respectively. Talaraculones A and B (1 and 2) exhibited stronger inhibitory activity against α-glucosidase than the positive control acarbose (IC50 = 101.5 μM), with IC50 values of 78.6 and 22.9 μM, respectively.