The optical properties and surface-enhanced Raman scattering (SERS) of plasmonic nanodome array (PNA) substrates in air and aqueous solution are investigated. PNA substrates are inexpensively and uniformly fabricated with a hot spot density of 6.25 × 106 mm−2 using a large-area nanoreplica moulding technique on a flexible plastic substrate. Both experimental measurement and numerical simulation results show that PNAs exhibit a radiative localized surface plasmon resonance (LSPR) due to dipolar coupling between neighboring nanodomes and a non-radiative surface plasmon resonance (SPR) resulting from the periodic array structure. The high spatial localization of electromagnetic field within the ∼10 nm nanogap together with the spectral alignment between the LSPR and excited and scattered light results in a reliable and reproducible spatially averaged SERS enhancement factor (EF) of 8.51 × 107 for Au-coated PNAs. The SERS enhancement is sufficient for a wide variety of biological and chemical sensing applications, including detection of common metabolites at physiologically relevant concentrations.