A fraction from an extract of the marine sponge Geodia microspinosa was identified as active in a high-throughput screen for molecules that impair the viability of diffuse pleural mesothelioma (DPM) cell lines. Bioassay-guided isolation led to the identification of microspinosamides B and D, and a new artifact, microspinosamide C, together with two previously reported analogues, microspinosamide and polydiscamide B, as the active principles. Their planar structures were solved by NMR and HRESIMS analyses, while advanced Marfey’s reaction, ROESY, and ECD were used for the establishment of their absolute configurations. All pure metabolites demonstrated low micromolar potency for the reduction in viability of the DPM cell lines.