A new nanocatalyst preparation pathway, using ultrasound, for potential application to an in-situ upgrading technology (ISUT) is investigated. An ultrasonic probe is employed for preparing the transient microemulsions of the molybdenum solution with vacuum residue (VR), while high-shear mixing is used for preparation of microemulsions of nickel solution in VR. The results of catalyst preparation showed that the synthesized NiMo nanoparticles are half the size of the particles prepared conventionally using a high shear mixer for both metal precursors. The two prepared batches of suspended nanocatalysts in VR were then tested for evaluating their activity for upgrading reactions. In the upgrading tests, VR + cat and hydrogen were injected into a reactor packed with silica sand, where temperature, pressure and residence time were 350 °C, 7 MPa g, and 48 h, respectively for all experiments. Appreciable activity enhancement was observed for the ultrasound-assisted prepared nanoparticles. Using the new preparation method, the density and viscosity, as well as coking tendency of the products decreased, while the demetallization and desulphurization extent were both enhanced. Therefore, further ultrasound-aided NiMo nanoparticle preparations were carried out to investigate the effect of input sonication energy on the particle size.