There were no reports on the anti-inflammatory effect of the seed of C. camphora (CCS) and the changes in the process of processing and consumption. The aim of the study was to investigate the anti-inflammatory activity of CCS ethanol extracts (EE), and the changes of it after simulated gastrointestinal digestion and alkaline hydrolysis in a lipopolysaccharide (LPS)-induced inflammatory macrophages model in vitro. The phytochemical characteristics of EE, digested ethanol extracts (dEE) and hydrolysed ethanol extracts (hEE) were analyzed using UPLC-LTQ-Orbitrap-MS/MS in this study, and 17 chemicals were tentatively identified from the three prepared samples. EE, dEE and hEE may have cell protection function, and both of them exhibited strong anti-inflammatory activity as significantly reduced multiple pro-inflammatory mediators and cytokines secretion and expression. Although the anti-inflammatory activity of EE was decreased by digestion and hydrolysis, and hydrolysis had more negative effect than digestion, most of its anti-inflammatory activity was retained. The mitigation of inflammation of EE may be by suppressing phosphorylation levels of signaling molecules of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways. The results suggest that the anti-inflammatory activity of EE is relatively stable undergo gastrointestinal digestion and alkaline hydrolysis, which may facilitate the processing and consumption of related products.