Five new metabolites, including three cyclic dipeptide derivatives (1–3) and two new polyketides (10–11), together with nine known ones (4–9 and 12–15), were isolated from the mangrove-sediments-derived fungus Talaromyces sp. SCSIO 41431. Their structures were determined using detailed NMR, MS spectroscopic analyses, and quantum chemical calculations. X-ray single-crystal diffraction analysis of 1 was described. Compounds 13–15 demonstrated activity against Staphylococcus aureus, with MIC values ranging from 25 to 50 µg/mL. Compound 9 showed activity against Escherichia coli, Streptococcus suis, and Erysipelothrix rhusiopathiae, with an MIC value of 100 µg/mL. In addition, compounds 1 and 12 showed DPPH radical scavenging activity, with the EC₅₀ of 27.62 and 29.34 µg/mL, compared to the positive control (ascorbic acid, EC₅₀, 12.74 µg/mL).