In conclusion, our investigation has shown the remarkable selectivity and efficiency of the immobilized lipase B from Candida antarctica (Novozym 435) in the esterification of sesquiterpene lactones (STLs), as well as the monoterpenoid perillyl alcohol, using vinyl esters as acyl donors. The methodology presented here allowed for the successful modification of Lc, DHLc, Lp, and DHLp, thereby demonstrating its broad applicability in the tailored functionalization of STLs. In addition, the study of the enzyme-substrate binding modes in the biocatalytic acylation of STLs brought us a more comprehensive understanding of their reactivity and the nature of the interactions with important amino acid residues in the active site of CAL-B. Further studies to expand the range of acyl donors and substrates, and to explore the optimization of reaction conditions, will open new avenues for the synthesis of STL derivatives, which could find extensive applications in medicinal chemistry and other fields.