<p>This study developed a nanozyme-SERS dual-function sensor that exhibits both highly efficient peroxidase (POD)-like activity and superior surface-enhanced Raman spectroscopy (SERS) enhancement, designed for detecting homocysteine (Hcy) in serum from colorectal cancer (CRC) patients. Bimetallic Au@Pt nanoparticles (Au@Pt NPs) exhibited exceptional nanozyme catalysis and SERS performance, enabling the oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) to oxidized TMB (oxTMB) with a pronounced SERS signal generation. Au@Pt NPs were assembled into aminated capillaries via electrostatic adsorption and subsequently modified with Hcy aptamers to create the nanozyme-SERS dual-function sensor. When Hcy was present, the reducing thiol groups (-SH) consumed the hydroxyl radicals (·OH) produced by the decomposition of H₂O₂. This inhibited the oxidation of TMB, resulting in a weaker SERS signal. The SERS sensor demonstrated a remarkably low detection limit (LOD) for Hcy, reaching as low as 0.14 × 10⁻¹² mol/L. Furthermore, within the concentration range of 10⁻¹² to 10⁻⁴ mol/L, there was a linear relationship between the logarithm of Hcy concentration and the SERS signal intensity. Serum samples from both healthy individuals and CRC patients were tested with the SERS sensor. The results demonstrated a high degree of concordance with those obtained by the enzyme-linked immunosorbent assay (ELISA), showing significantly higher Hcy levels in CRC patient serum compared to healthy controls. Unlike traditional methods such as colorimetric assays, fluorescence analysis, and the SERS “sandwich” strategy, which often involve complex procedures and have low sensitivity, this approach offers a simple, highly sensitive, and specific method for detecting Hcy. It holds promise as an effective tool for early CRC diagnosis.</p>