Surface-enhanced　Raman　spectroscopy　(SERS)　is　a　powerful　optical　technique　with　high　sensitivity　to　identify　analytes　down　to　a　single　molecule　by　fingerprinting　vibrational　information.　The　strong　coupling　in　microcavities　for　supermodes　with　promoted　quality　factors　demonstrates　the　capability　to　boost　the　interaction　between　photons　and　molecules　for　nonlinear　effects.　Here　a　strong-coupling　cascade　microsphere-cavity　(MC)　achieving　spontaneous　Raman　enhancement　is　reported,　for　the　first　time.　The　cascade　MC　is　composed　of　two　size-mismatched　microspheres,　both　of　which　support　optical　whispering-gallery　modes　(WGMs)　with　significantly　different　free-space　ranges.　The　strong　coupling　between　the　supported　WGMs　in　the　microspheres　can　be　achieved　when　the　quasi-vernier　effect　of　resonant　modes　occurs,　by　which　the　energy　splitting　is　up　to　4　meV.　The　fast　energy　transfer　between　the　size-mismatched　MCs　therefore　increases　the　quality　factor　up　to　2.1　x　103　for　the　upper　supermode　branch.　The　strong-coupling　cascade　MC　structure　provides　an　extra　enhancement　channel　for　the　Au-based　SERS　substrate,　demonstrating　an　enhancement　factor　of　Raman　intensity　(EFRI)　up　to　2.6　x　1010　for　the　limit　of　detection　(LoD)　down　to　10-12　M　of　4-aminothiophenol　(4-ATP).　The　strong-coupling　cascade　MC　substrates　also　exhibit　the　versatility　for　identification　of　multiple　analytes　for　high-performance　Raman　trace-detection　applications.　A　cascade　microsphere-cavity　structure,　composed　of　two　size-mismatched　microspheres　supporting　optical　whispering-gallery　modes　with　significantly　different　free-space　ranges,　is　developed　to　achieve　strong-coupling-enhanced　Raman　spectroscopy　(SCERS).　It　provides　an　extra　enhancement　channel　in　addition　to　traditional　SERS　substrate　with　an　enhancement　factor　up　to　2.6　x　1010　for　the　limit　of　detection　down　to　10-12　M　of　4-aminothiophenol.　image