Coal tar asphaltene (CT-asp) is one of the important heavy components of coal tar. It has significant influences on the conversion efficiency of slurry-phase hydrocracking. The reactivity and structure changes of CT-asp in a slurry-phase process were investigated. Experimental results showed that the conversion of CT-asp reached 66.5 wt % with a significant decrease of sulfur and oxygen contents as the reaction time increased. The CT-asp obtained from the hydrocracking reaction carried out for different time has been analyzed by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, X-ray diffraction, and H-1/C-13 nuclear magnetic resonance. The chemical structural analysis results confirmed that CT-asp was mainly composed of more aromatic rings with oxygen functional groups and possessed a higher aromaticity and shorter aliphatic chains after hydrocracking. Moreover, the effective cracking of carbonyl groups, pyrrolic nitrogen, and alkyl sulfides in CT-asp was found during the slurry-phase hydrocracking. It was considered that a structure with an average of two aromatic rings per aromatic sheet existed in the average molecule of CT-asp, and the aromatic sheets were condensed with each other through diphenyl-like structures or oxo-bridged linkages. In addition, a free radical reaction pathway of CT-asp in slurry-phase hydrocracking was proposed on the basis of the main detected products and the molecular structural changes.