This work investigates the influence of active site size in dispersed MoS2 on the slurry-phase hydrocracking of Merey residue (MRR). MoS2 nanocatalysts with varying morphologies were synthesized using the ligand sulfurization method, employing molybdenum oleate as the Mo precursor. The results demonstrate that mono-layered or double-layered MoS2 plates with slab sizes of 3 ∼ 10 nm can be synthesized at a sulfurization temperature of 400 °C and a sulfurization time of 0.5 h. Prolonged sulfurization time results in the growth and agglomeration of MoS2 plates, leading to multi-layered slabs with increased length and larger particle size, as well as a wider distribution range. The MoS2-0.5 (prepared with a sulfurization time of 0.5 h) exhibits superior hydrocracking activity, effectively converting resin and asphaltene into light fractions and significantly suppressing coke formation. Specifically, the conversion rates of resin and asphaltene are 51.3 wt% and 92.1 wt%, respectively, with the minimal coke yield of 0.6 wt% under conditions of 430 °C, 1 h, 7 MPa initial H2, and a catalyst dosage of 500 μg/g. The catalytic activity of the MoS2 nanocatalysts exhibits a strong correlation with their size and morphology obtained at different sulfurization times. Density functional theory (DFT) calculations reveal that MoS2 with smaller slab sizes are more beneficial for the adsorption and dissociation of H2, due to higher adsorption energy (Eads) and lower activation barrier (Ea). This facilitates the generation of sufficient active hydrogen to encourage the hydrocracking of residue and suppress coke formation.