Taiwan zelkova (Zelkova serrata (Thunb.) Makino) is one of the five most precious hardwood trees in Taiwan, and is also a medical plant based on traditional knowledge. The aim of this study was to evaluate antioxidant and antiinflammatoy activities of essential oils and ethanolic extracts from three plant parts (heartwood, sapwood, and bark) of Z. serrata. In addition, the potential to delay the ageing process and to protect against amyloid-β toxicity of essential oils and ethanolic extracts from Z. serrata were investigated in the model organism Caenorhabditis elegans. Results obtained from in vitro assays demonstrated that the essential oil of Z. serrata heartwood exhibited good radical scavenging activities and high total phenolic content (161.4 mg of GAE/g). The bark extract contained the highest level of total phenolic content (288.1 mg of GAE/g), and possessed excellent free radical scavenging activities and reducing power, but bark extract did not exhibit antiinflammatoy activity. The heartwood extract contained high levels of total phenolic (234.8 mg of GAE/g) and total flavonoid contents (348.5 mg of RE/g), and had both antioxidant and antiinflammatoy activities. The antioxidant and antiinflammatoy activities of 4 soluble fractions from heartwood extract were further examined. Results showed that the ethyl acetate soluble fraction had the highest yield and good antioxidant activities, but no antiinflammatoy potential. The n-hexane soluble fraction had high yield as well as good antioxidant and antiinflammatory activities. In vivo assays showed the essential oil of heartwood significantly inhibited oxidative damage in wild-type C. elegans (N2 strain) under juglone-induced oxidative stress and heat shock. The heartwood extract, its soluble fractions and subfraction E10 also significantly increased stress resistance to juglone and heat stress in wild-type C. elegans. 17 compounds, including 15 sesquiterpenes and 2 flavonoids, were obtained from essential oil and extract of heartwood after a bio-guided fractionation. 7-Methoxyzelkoserratone (4), 3-hydroxy-7-methoxy-3(4H)-isocadalen-4-one (5), 4-methoxymansonone G (6), 6-hydroxy-5-isopropyl-2,8-dimethyl-2,3-dihydro-[1,4] naphthoquinone (8), 4,7-dihydroxy-calamenen-3-one (10), 3-methoxy-7-hydroxy- 3(4H)-isocadalen-4-one (11), and 1α-hydroxy-7-methoxy-1(4H)-isocadalen-4-one (12) were firstly isolated from nature. 7-Hydrxycalamenene (1), 7-hydroxycadalene (2), 7-hydroxy-calamenen-3-one (9), 3,7-dihydroxy-3(4H)-isocadalen-4-one (13), and mansonone G (15) were isolated from Z. serrata for the first time. In vitro assays showed that 7-hydroxycalamenene (1), 7-hydroxy- 3-methoxycadalene (3), and kaempferol-6-C-glucoside (17) exhibited antioxidant activities; 7-hydroxy-3-methoxycadalene (3), 7-hydroxy-calamenen-3-one (9), and 3,7-dihydroxy-3(4H)-isocadalen-4-one (13) had anti-inflammatory activities. Additionally, the major compound in essential oil of heartwood, 7-hydroxycalamenene, may contribute significantly to the observed antioxidant activity. Further evidence showed that 7-hydroxycalamenene (1) significantly delayed the paralysis phenotype in amyloid beta-expressing transgenic C. elegans (CL4176 strain), revealing that the potential for drugs dietary supplements to slow progress of Alzheimer’s disease. The major compound in subfraction E10 of heartwood extract, kaempferol-6-C-glucoside (17), slightly extended the lifespan of wild-type C. elegans but did not affect the aging behaviors under normal condition. However, kaempferol-6-C-glucoside (17) significantly increased the longevity of wild-type C. elegans under juglone-induced oxidative and thermal stresses. Furthermore, results revealed that kaempferol-6-C-glucoside (17) enhanced the translocations of the transcription factors DAF-16 (dauer formation-16) and SKN-1 (skinhead-1), thereby up-regulating the downstream gene expression of stress response proteins SOD-3 (superoxide dismutase-3) and GST-4 (glutathione S-transferase-4), respectively, to enhance the stress resistance in C. elegans. The study demonstrated the essential oils and extracts of Z. serrata exhibited in vitro and in vivo antioxidant activities, and has potential to be used as a source for treatment of Alzheimer’s disease. These findings suggest that the extractives from Z. serrata heartwood has potential to be used as health-care food or drug for antioxidant or Alzheimer’s disease treatment.