Six new depsidones, curdepsidones B−G (1−6), were obtained from the marine-derived fungus Curvularia sp. IFB-Z10. Their planar structures were determined by comprehensive analysis of HRESIMS and 1D/2D-NMR data. The absolute configuration of curdepsidones B−C (1−2) were established by synergistic use of DFT/NMR (density functional theory/nuclear magnetic resonance) and TDDFT/ECD (time-dependent density functional theory/electronic circular dichroism) calculations. Partial isolated compounds were tested for their anti-inflammatory activities in Propionibacterium acnes-induced THP-1 cells. Curdepsidone C (2) displayed significant anti-inflammatory properties with an IC50 value of 7.47 ± 0.35 μM, and reduced the P. acnes-induced phosphorylation levels of JNK and ERK in a dose-dependent mechanism. The possible anti-inflammatory mechanism of 2 was also investigated by molecular docking.