The effects of various organic solvents having different H-donor index, asphaltene solubility, and alkyl-substitution on the upgrading of vacuum residue (VR) were investigated under thermal cracking or catalytic hydrocracking conditions at 673 K and 10.0 MPa N-2 or H-2. Molecular dynamics simulations were also adopted to verify physical interaction between asphaltene species with H-donor solvents. Thermal cracking led to a considerable amount of coke formation, close to 29.8 wt.%, but the addition of H-donors reduced the coke formation down to 23.4, 19.0, 12.4, and 4.1 wt.% in the presence of naphthalene, 1-methyl naphthalene(1-MN), decalin, and tetralin, respectively. The coke formation was considerably reduced to 7.2 wt.% in the hydrocracking condition, and further down to 2.9 and 1.2 wt.% in the presence of naphthalene and tetralin, respectively. It was demonstrated that H-donors retaining the H transfer capability coupled with the solubility of asphaltene contributed to the marked performance of VR hydrocracking in the presence of dispersed MoS2 catalyst.