Thuwalamides A–E (1, 3, 5, 6 and 8), previously undescribed polychlorinated amides, along with ten previously reported related compounds (2, 4, 7 and 9–15), were isolated from the organic extract of the marine sponge Lamellodysidea herbacea (Keller), collected off the village of Thuwal in the Red Sea at Saudi Arabia. The structures of the isolated compounds have been determined through extensive analysis of their NMR and MS data, while their absolute stereochemistry was unequivocally established via single crystal X-ray diffraction. Additionally, the absolute stereochemistry of the previously reported compounds 2 and 4, whose configuration was not determined, has also been established using single-crystal X-ray crystallographic analysis. The antibacterial activity of compounds 1–15 was evaluated against Escherichia coli and Staphylococcus aureus. Among them, compound 14 displayed activity against S. aureus comparable to vancomycin that was used as a positive control with a MIC value of 4 μg/mL.