A new scalarane-type sesterterpene, 12-deacetoxyscalarin 19-acetate (2), and two naturally new derivatives of manoalide-type sesterterpenes, (E)- and (Z)-neomanoalide 24,25-diacetates (3 and 4), were isolated from the Thai sponge Brachiaster sp., along with five other known sesterterpenes: heteronemin (1), heteronemin acetate (5), 12-epi-19-deoxyscalarin (6), 12-deacetyl-12-epi-19-deoxyscalarin (7), and manoalide 25-acetate (8). The antitubercular and cytotoxic activities of all eight compounds were evaluated to reveal the potent activity of compounds 1, 2, 5, and 8. Among these, compound 2 showed an interesting bioactivity profile, in possessing potent antitubercular activity and being practically inactive in the cytotoxicity bioassay.