Nano Cr2O3 (n-Cr2O3) was prepared by the thermolysis of the mesoporous Cr-MIL-101, and its catalytic performance for n-hexane dehydrogenation was investigated and compared with Cr2O3 obtained by traditional method. It is found that dehydrogenation of n-hexane on n-Cr2O3 catalyst can produce n-hexenes and benzene efficiently, and the catalytic performance is related to the calcination temperature. The optimal n-hexane conversion can be obtained on n-Cr2O3 calcinated under 600 °C, is 40.6%, and the selectivities to n-hexenes and benzene are 20.1% and 69.3%, respectively. The conversion of n-hexane for n-Cr2O3 catalyst is decreased with calcination temperature increase, while the catalyst stability in dehydrogenation reaction is enhanced. n-Hexane conversion of p-Cr2O3-1 (obtained by precipitation method) and p-Cr2O3-2 (calcinating Cr(NO3)·9H2O directly) catalysts are very low (<7.5%), and their specific activity for n-hexane dehydrogenation are 1.5 and 1.7 g/(m2·h) respectively, lower than that of n-Cr2O3-600 (2.0 g/(m2·h)). The results of BET, XRD, TEM and FT-IR reveal that n-Cr2O3 is the nanoparticles with large specific surface area that more dehydrogenation active sites are exposed, while p-Cr2O3 is the large particles with extremely low surface area that few dehydrogenation active sites are presented. By contrast, industrial Cr2O3/Al2O3 catalyst possesses the highest specific activity of 2.4 g/(m2·h) due to the dispersion effect of Al2O3. Therefore, highly catalytic activity of n-Cr2O3 for n-hexane dehydrogenation is attributed to the unique properties of small particle, large specific surface area and more exposed active sites. This work not only explains the high dehydrogenation activity of nano-Cr2O3 derived by Cr-MIL-101, but also provides guidance for the precise design and synthesis of high-performance CrOx-based catalyst for the dehydrogenation of alkanes.