Several rare-earth oxides, prepared through a hydrothermal process, were employed as catalysts for vapor-phase dehydration of 3-methyl-1,3-butanediol (3MBDO) to isoprene. Ytterbium oxide (Yb2O3) emerged as the most efficient catalyst for the dehydration of 3MBDO to isoprene. The hydrothermal time and calcination temperature influenced the performance of Yb2O3. The reaction temperature and contact time strongly affect the dehydration of 3MBDO and unsaturated alcohols, while the major side reaction of isobutene formation via decomposition of 3-methyl-3-butene-1-ol was mainly influenced by the reaction temperature. The highest isoprene yield of 92% was achieved at 450 °C and a long contact time of 3.75 h. The poisoning experiment using CO2, 2,6-, and 3,5-dimethylpyridine revealed the importance of base and acid sites of Yb2O3 in the dehydration of 3MBDO, indicating the dehydration of 3MBDO to isoprene proceeded via an acid-base concerted mechanism.