Inflammatory processes are renowned as the fundamental basis for numerous pathological conditions. The objective of this study was to assess the antioxidant, anti-inflammatory, molecular docking, and molecular dynamics simulation properties of 3 previously undescribed and 1 known guaiane-type sesquiterpenoids isolated from Cinnamomum migao. The structures of these compounds were confirmed using numerous chromatographic and spectroscopic methods, such as high-resolution electrospray ionization mass spectrometry (HRESIMS), one-dimensional nuclear magnetic resonance (1D NMR), two-dimensional nuclear magnetic resonance (2D NMR), and experimental circular dichroism (ECD). Additionally, in oxidatively stressed mouse hepatocytes, all tested compounds at a concentration of 50 µM increased the levels of natural antioxidant enzymes such as CAT, SOD, POD, and Nrf-2 compared to those in untreated cells. Compounds 1 and 2 strongly suppressed NO generation and proinflammatory cytokine production, with IC50 values of 8.76 and 5.45 µM, respectively, against TNF-α mRNA. Furthermore, the molecular docking and simulations explore the high affinity of the selected compounds and best fit in the TNF-α active site. Compounds 1 and 2 show prominent binding energies and bring significant confirmational changes in the TNF-α protein. The results of this study provide further validation for the traditional use of C. migao in the treatment of inflammation and pain, providing novel evidence regarding the therapeutic potential of the identified guaiane-type sesquiterpenoids.