Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common metabolic disorder in which the gut–liver axis plays a key role. Titanium dioxide nanoparticles (TiO₂), common food additives, may affect gut microbiota and health. This study investigates the role of Akkermansia muciniphila and its outer membrane vesicles (OMVs) in TiO₂-induced MAFLD under a high-fat diet (HFD). Methods: Low-dose TiO₂ was co-incubated with A. muciniphila to assess its effects on growth and OMV production. OMVs derived from TiO₂-treated A. muciniphila were then co-cultured with hepatocytes to assess their impact on lipid accumulation. In vivo, mice were fed control or HFD with/without TiO₂ for 13 weeks. Hepatic lipid deposition, inflammatory cytokines, intestinal barrier integrity, and gut microbiota composition were assessed. Fecal OMVs were isolated for proteomic analysis and integrated with hepatic metabolomics to explore regulatory pathways. In the next experiment, mice were divided into HFD, HFD+TiO₂, HFD+A. muciniphila, and HFD+TiO₂+A. muciniphila groups to assess the protective effects of A. muciniphila. Results: Low-dose TiO₂ promoted A. muciniphila growth and OMV production. OMVs from TiO₂-treated bacteria reduced lipid accumulation in hepatocytes. TiO₂ reduced hepatic lipids under the control diet but exacerbated steatosis and inflammation under the HFD, associated with altered lipid metabolism genes and an impaired intestinal barrier. Metagenomic analysis showed that TiO₂ reshaped gut microbiota, increasing A. muciniphila under the control diet but decreasing it under the HFD. OMV proteomics and liver metabolomics revealed enrichment in lipid and energy metabolism pathways. Supplementation with A. muciniphila alleviated TiO₂-aggravated hepatic lipid accumulation in vivo. Conclusion: TiO₂ exacerbates HFD-induced MAFLD by altering gut microbiota, impairing gut barrier function, and promoting hepatic lipid accumulation and inflammation. Under the control diet, TiO₂ increases A. muciniphila, reducing hepatic lipid accumulation. Supplementation with A. muciniphila and its OMVs reverses these effects, suggesting TiO₂ may influence MAFLD progression via the modulation of specific gut microbes.