This paper deals with the calculation of isomerization reactions of 2-pentoxy radical and its derivatives (including unsaturated alkoxy radicals) by density functional theory. The results indicate that the process via six-membered ring TS calculated at the B3LYP/6-311++G** level for 2-pentoxy had the lowest energy barrier, 8.63 kcal/mol. However, in the unsaturated derivatives, the energy barriers very much depend on the double bond position in the molecule, and that may alter the isomerization processes. The substitution effect on the isomerization barrier was as well investigated. The calculated lowest energy barrier of the substituted compound of 2-pentoxy was 3.77 kcal/mol of 5,5-dimethyl-2-pentoxy radical. We found that the relative stability of the isomerization products was one of the important factors concerning the barrier. Usually, the isomerization takes place via a six-membered TS to have almost free ring-strain energy. Nevertheless, our calculation shows that it is possible to find the substituted unsaturated alkoxy derivatives to proceed via a smaller ring transition structure (five-membered, instead of six-membered) to have lower energy barrier.