Cinnamomum cassia Presl. (Lauaceace) has been used as flavor additive for foods and traditional medicine for thousands of years. However, the bio-active compounds from Cinnamomum cassia are still not fully understood. In this study, a series of column chromatographic methods monitored with UPLC-TOF-MS were applied to isolate the compouds from the twigs of Cinnamomum cassia. Their structures were elucidated by NMR and HRMS spectroscopic data, calculated ECD and CD experiments analyses. Furthermore, the neuroprotective activities were identified on endoplasmic reticulum (ER) stress-induced neural cell injure models. As a result, 7 new α, β-diphenyl-γ-butyrolactones, 3 new lignans, 5 new neolignans, 2 new biphenylpropanoids and a new flavonol glycoside-lignan ester, together with 43 known compounds were isolated from the twigs of Cinnamomum cassia, among which compounds 11 and 12 are novel neolignans possessing a dioxetane ring. Pretreatment with compounds 11 and 12 significantly reduced the ER stress-induced neuron cytotoxicity on SH-SY5Y cells. In conclusion, compounds 11 and 12 are new natural products and may be developed as a new type of neuroprotective agents.