To improve both sensitivity and reliability, a hybrid SERS substrate of combining gold nanoislands (GNI) with periodic MgF2 nanopillar arrays was successfully developed. SERS detection performance of the proposed substrates was evaluated in terms of enhancement effect, signal-to-noise ratio (SNR), linearity, reproducibility and repeatability, and compared with the performance of a conventional SERS substrate based on GNI. Experimental and simulation results presented that significant improvement of SERS intensity and SNR by more than 3 times and a notable reduction in relative standard deviation were obtained. We hope that the suggested SERS platform with unique advantages in sensitivity and reliability could be extended to point-of-care detection of a variety of biomolecular reactions.