The coke formation, liquid product distribution, alterations in catalytic active sites, and variations of residue colloidal stability were analyzed to investigate the additive effect of iron(III) dodecylbenzenesulfonate (IDBS) with an oil-soluble Mo catalyst in slurry-phase hydrocracking of Venezuela fuel oil (VFO). Experiments demonstrated that IDBS as well as polyoxyethylenesorbitan monooleate (Tween 80) and sodium dodecylbenzenesulfonate (SDBS) for comparison could separately promote the amount of suspended coke and reduce the sedimentary coke on the surface of the reactor, while changes in total coke were minor. In the presence of the Mo catalyst, IDBS showed a significant synergy effect with the Mo catalyst on mitigating the coke formation in contrast to Tween 80 and SDBS. The sulfidity of the Mo catalyst and catalytic active centers for hydrogenation were facilitated using IDBS, according to the analyses of the X-ray fluorescence (XRF) determination and X-ray diffraction (XRD) spectroscopy. In addition, analyses of saturate, aromatic, resin, and asphaltene (SARA) composition, collodial stability parameter (CSP), and coking inducing period, together with Fourier transform infrared (FTIR) spectroscopy, indicated the improvement of colloidal stability when IDBS was added. Micromorphology and sizes of coke were compared via scanning electron microscopy (SEM) and laser particle size analysis (LPSA), respectively, confirming that the synergism between IDBS and the Mo catalyst decreased the total coke and improved the dispersity of coke in slurry-phase hydrocracking.