To treat acne more efficiently, we have synthesized ceria/silica nanoparticles with improved physicochemical and biological properties to enhance topical delivery of isotretinoin. Two types of nanoparticles were synthesized by the sol–gel and co-precipitation methodologies, namely silica containing 10% ceria (SC2 10%) and ceria (C2). SC2 10% and C2 were incorporated with isotretinoin (diluted in dimethylsulfoxide) at a 1:1 (m/m) ratio for 24 h, to give SC2 10%-ISO and C2-ISO, respectively. The nanoparticles had high elemental purity and polydispersity index lower than 0.7. SC2 10% comprised spherical nanoparticles measuring around 300 nm, whereas C2 consisted of agglomerated nanocrystallites with mean diameter ranging from 303 to 515 nm. SC2 10% and C2 had negative (-33.0 mV) and positive (+30.7 mV) zeta potential, respectively. The ISO immobilization efficiency was 11% for SC2 10%-ISO and 16% for C2-ISO, as revealed by indirect quantification by HPLC. An in-vitro drug release study showed that C2-ISO released 16 μg of ISO within 48 h. The cell viability results obtained in HaCat cell culture showed that ISO kept nanoparticle cytotoxicity low, as revealed by XTT assays. Minimum inhibitory concentration assays demonstrated that both SC2 10%-ISO and C2-ISO inhibited Cutibacterium acnes growth, indicating combined action of the drug and nanoparticle matrix. Therefore, ceria-based nanoparticles proved a promising alternative for transporting ISO and promoting its controlled and targeted release: the nanoparticles were chemically stable, presented suitable dispersion characteristics, and inhibited bacterial growth.