High-fat diet (HFD)-fed mice show obesity with development of liver steatosis and a proinflammatory state without establishing an inflammatory reaction. The aim of this work was to assess the hypothesis that eicosapentaenoic acid (EPA) plus hydroxytyrosol (HT) supplementation prevents the inflammatory reaction through enhancement in the hepatic resolvin content in HFD-fed mice. Male C57BL/6J mice were fed an HFD or a control diet and supplemented with EPA (50 mg/kg/day) and HT (5 mg/kg/day) or their respective vehicles for 12 weeks. Measurements include liver levels of EPA, DHA and palmitate (gas chromatography), liver resolvins and triglyceride (TG) and serum aspartate transaminase (AST) (specific kits) and hepatic and serum inflammatory markers (quantitative polymerase chain reaction and enzyme-linked immunosorbent assay). Compared to CD, HFD induced body weight gain, liver steatosis and TG accumulation, with up-regulation of proinflammatory markers in the absence of histological inflammation or serum AST changes; these results were accompanied by higher hepatic levels of resolvins RvE1, RvE2, RvD1 and RvD2, with decreases in EPA and DHA contents. EPA+HT supplementation in HFD feeding synergistically reduced the steatosis score over individual treatments and increased the hepatic levels of EPA, DHA and resolvins, with attenuation of proinflammatory markers. Lack of progression of HFD-induced proinflammatory state into overt inflammation is associated with resolvin up-regulation, which is further increased by EPA+HT supplementation eliciting steatosis attenuation. These findings point to the importance of combined protocols in hepatoprotection due to the involvement of cross-talk mechanisms, which increase effectiveness and diminish dosages, avoiding undesirable effects.