Surface enhanced resonance Raman scattering (SERRS) is a physical phenomenon that occurs when the energy of incident light is close to that of electronic excitation of reporter molecules (RMs) attached on substrates. SERRS has showed great promise in healthcare applications such as tumor diagnosis, image-guided tumor surgery and real-time evaluation of therapeutic response due to its ultra-sensitivity, manipulating convenience and easy accessibility. As the most widely used organic near-infrared (NIR) fluorophore, heptamethine cyanines possess the electronic excitation energy that is close to the plasmon absorption energy of the gold nano-scaffolds, which results in the extraordinary enhancement of the SERRS signal. However, the effect of heptamethine cyanine structure and the gold nanoparticle morphology to the SERRS intensity are barely investigated. This work developed a series of SERRS nanoprobes in which two heptamethine cyanine derivatives (IR783 and IR780) were used as the RM and three gold nanoparticles (nanorod, nanosphere and nanostar) were used as the substrates. Interestingly, even though IR780 and IR783 possess very similar chemical structure, SERRS signal produced by IR780 was determined as 14 times higher than that of IR783 when the RM concentration was 6:5 × 10⁶ M. In contrast, less than 4.0 fold SERRS signal intensity increase was measured by changing the substrate morphologies. Above experimental results indicate that finely tuning the chemical structure of the heptamethine cyanine could be a feasible way to develop robust SERRS probes to visualize tumor or guide tumor resection with high sensitivity and target to background ratio.