A hollow core micro-bottle cavity (HC-MBC) biosensor with high quality ( Q ) factor for DNA detection with low detection limit has been proposed and demonstrated. Whispering gallery mode (WGM) spectra with Q factor >10 6 are excited through high-precision coupling of tapered fiber and HC-MBC. An improved surface functionalization method is used at 70 °C to ensure binding of probe single-stranded DNA onto the inner surface of the HC-MBC with high effectiveness and stability. Based on the principle of base complementary pairing, efficient detection of DNA with different concentrations and sequences are realized. The detection volume and limit of the proposed biosensor are ∼ nL and pM, respectively. Single-nucleotide mismatch recognition is also achieved. Benefiting from its label free, compact size, real-time and low detection limit, the proposed biosensor has broad application prospects in bioengineering and medical diagnosis.