Lung cancer is the leading cause of cancer death worldwide. Its early detection is of paramount importance for diagnosis, classification, treatment, and improvement of survivorship. However, current methods are not sensitive enough to detect lung cancer in its nascent stage. We reported an aptamer–Ag–Au shell–core nanostructure-based surface-enhanced Raman scattering (SERS) assay for sensitive and specific detection, and near-infrared (NIR) photothermal therapy of lung adenocarcinoma cells (A549 cells). The nanostructures target the cells with high affinity and specificity via the specific interaction between the aptamer (a 45-base oligonucleotide) and the cell, and distinguish A549 cells from other types of cancer cells (HeLa and MCF-7 cells) and subtypes of lung cancer cells (NCI-H157, NCI-H520, NCI-H1299, and NCI-H446 cells). The nanostructures have a high capability to absorb NIR irradiation and are able to perform photothermal therapy of the cells at a very low irradiation power density (0.20 W cm⁻²) without destroying the healthy cells and the surrounding normal tissues. In addition, the nanostructures exhibit a high SERS activity. Based on the SERS signal of the labeled Raman reporter (Rh6G molecules), we can specifically detect A549 cells at a very low abundance (∼10 cells per mL) and monitor the therapy process of the cancer cells. Therefore, this nanostructure-based SERS assay has great potential in specific recognition, sensitive detection, and effective photothermal therapy of lung cancer.