In this study, chlorogenic acid (CA) was acylated with vinyl esters of different carbon chain lengths under the action of the lipase Lipozyme RM. Five CA derivatives (C2-CA, C4-CA, C6-CA, C8-CA, and C12-CA) with different lipophilicities were obtained, and their digestive stabilities and antioxidant activities were evaluated. The lipophilicities were positively correlated with the digestive stabilities of CA derivatives. The antioxidant activities of CA derivatives did not change with the reduction of phenolic hydroxyl groups, and their capacity to scavenge 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS⁺•) and 1,1-diphenyl-2-picrylhydrazyl (DPPH•) were similar to those of CA. In cellular antioxidant activity (CAA) tests, it was found that the capacity of these derivates to cross cell membranes were enhanced upon enhancing lipophilicity, and their antioxidant activities were improved. C12-CA showed the best antioxidant activity with a median effective dose (EC₅₀) of 9.40 μg/mL, which was significantly lower than that of CA (i.e., 29.08 μg/mL).