Single crystal diamond (SCD) is an ultra-hard semiconductor material with exceptional chemical inertness, posing challenges for conventional oxidants to induce oxidation. The highly electronegative and potent ·OH produced by the Fenton reaction possesses significant importance in enabling efficient and high-quality polishing of SCD. This study delved into optimizing the Fenton reaction polishing slurry through orthogonal experiments and explored its influence on SCD CMP concerning various mechanical factors. Findings indicated that pH value, Fe3O4 concentration, and H2O2 concentration had a significant impact on the material removal rate (MRR) and surface roughness of SCD CMP, with Fe3O4 particle size playing a comparatively minor role. The optimized Fenton reaction polishing slurry achieved a peak MRR of 742.7 nm/h and a minimum surface roughness Ra of 0.240 nm. The acidic Fenton reaction polishing slurry generated H+ and ·OH, which interacted with the surface of SCD, forming an oxidation layer consisting of C–O/C–H and CO groups, thereby facilitating SCD material removal. This study provides a theoretical basis for the broader application of the Fenton reaction in SCD CMP at scale.