One new bisesquiterpenoid, biepiasreorlid II (1), three new sesquiterpene lactones 8α-methoxy-epiasterolid (4), 3β-acetoxyl-8-epiasterolid (5), and 3β-acetoxyl-atractylenolide I (6), along with five known analogues (2–3 and 7–9), were obtained from rhizome of Atractylodes macrocephala Koidz. All structures were assigned on the basis of detailed spectroscopic analyses. The absolute configuration of 1 was established by the analysis of single-crystal X-ray diffraction with Ga Kα radiation, and 4–6 were elucidated by TDDFT-ECD calculations. The CREB agonistic activity was investigated in HEK293T cells using dual luciferase reporter assay. Compounds 1, 2, 5, and 7–9 exhibited strong to agonistic activities on CREB.