Metastable oxide phases containing coordinatively unsaturated metal sites are highly active in many catalytic reactions. The stabilization of these nanostructures during reactions remains a major challenge. Here, we show that metastable two-dimensional (2D) FeO structures can be grown on Pt(111) and Au(111), but not on the graphene surface. The well-defined 2D structure is achieved by an interface confinement effect originating from the strong interfacial bonding between Fe atoms and substrate surface atoms. The stabilization effect has been described by the interface confinement energy (Econfinement), which is the energy difference lowered by interfacing the 2D structure with a substrate and decreases in the sequence of Pt(111) > Au(111) > graphene. This interface effect is widely present in many metal-oxide composite catalysts and can be used to guide the rational design of catalytically active sites.