Five new sesquiterpenes, named lingshuiolides A (1) and B (2), lingshuiperoxide (6), isodysetherin (10), and spirolingshuiolide (12), along with several known related analogues (7- 9, 11, and 13- 15), were isolated from the Hainan marine sponge Dysidea septosa. The structures of new compounds 1, 2, 6, 10, and 12 were determined by detailed analysis of 1D and 2D NMR spectra and by comparison with related model compounds. The absolute configuration of lingshuiolide B (2) was established by using the modified Mosher's method. Spirolingshuiolide (12) represents the first example of a sesquiterpene with a rearranged drimane skeleton. Compounds 7- 9 and 15 exhibited significant inhibitory activity against human protein tyrosine phosphatase 1B (hPTP1B), an enzyme involved in the regulation of insulin signaling. In particular, 15 showed the most potent effect, with an IC 50 value of 1.9 microg/mL.