This study evaluated the effect of two antagonist substrates (Y-TZP/zirconia or stainless steel) on the wear rate and surface alterations of different composite materials and bovine tooth substrates (enamel and dentin). The wear rate of different composite materials (n = 20; two direct composite resins: HelioMolar - HM; Clearfil AP-X - CAP, three indirect composite resins: Estenia C&B - EST; Adoro - ADO; Sinfony - SFY, and one composite resin for direct/indirect restorations: Filtek Z250 - Z250), bovine enamel and dentin against two different antagonist materials (zirconia or stainless steel) into two mediums (two-body and three-body wear) were collected. After wear tests on ACTA wear machine, Scanning Electron Microscopy (SEM) analysis was performed to access the surface alterations. The wear data were evaluated by three-way ANOVA and Tukey post-hoc test (α = 0.05). The factors 'antagonist', 'medium', 'restorative materials', and the interaction of all factors grouped by two and integrated showed statistical significance on the wear rates. A two-body test depicted no difference among all composites and enamel for wear rate, while a three-body test depicted differences among composites directly related to the filler content: EST < Z250 = CAP < ADO = HM < SFY. Dentin always showed the highest wear rates and enamel the lowest rates. The presence of food bolus (three-body test) led to higher wear rates in comparison to an only aqueous medium (two-body test). SEM analysis showed that different materials present specific wear patterns, regardless of the medium and the antagonist considered. Differently from enamel, dentin substrate was intensively prone to wear, regardless of the antagonist/medium. Resin composite substrates presented intermediate wear rates, depending directly on their filler content (% in weight).