Development of efficient catalysts with high atomic utilization and turnover frequency (TOF) for H2 activation in slurry phase hydrocracking (SPHC) is crucial for the conversion of vacuum residue (VR). Herein, for the first time, we reported a robust and stable single atoms (SAs) Mo catalyst through a polymerization-pyrolysis-in situ sulfurization strategy for activating H2 in SPHC of VR. An interesting atomic coordination structural dynamic evolution of Mo active sites was discovered. During hydrocracking of VR, the O atoms that coordinated with Mo were gradually replaced by S atoms, which led to the O/S exchange process. The coordination structure of the Mo SAs changed from pre-reaction Mo-O3S1 to post-reaction Mo-O1S3 coordination configurations, promoting the efficient homolytic cleavage activation of H2 into H radical species effectively. The evolved Mo SAs catalyst exhibited robust catalytic hydrogenation activity with the per pass conversion of VR of 65 wt%, product yield of liquid oils of 93 wt%, coke content of only 0.63 wt%, TOF calculated for total metals up to 0.35 s−1, and good cyclic stability. Theoretical calculation reveals that the significant variation of occupied Mo 4d states before and after H2 interaction has a direct bearing on the dynamic evolution of Mo SAs catalyst structure. The lower d-band center of Mo-O1S3 site indicates that atomic H diffusion is easy, which is conducive to catalytic hydrogenation. The finding of this study is of great significance to the development of high atom economy catalysts for the industrial application of heavy oil upgrading technology.