Opioid misuse and overdose have caused devastating public health challenges and economic burdens, calling for the need of rapid, accurate sensitive opioid sensors. Here, we report a photonic crystal-based opioid sensor in the total internal reflection configuration, providing label-free, rapid, quantitative measurements through change of the refractive index. The one-dimensional photonic crystal with a defect layer that is immobilized with opioid antibodies acts as a resonator with an open microcavity. The highly accessible structure responds to analytes within a minute after the aqueous opioid solution is introduced, achieving the highest sensitivity of 5688.8 nm/refractive index unit (RIU) at the incident angle of 63.03°. Our sensor shows a limit of detection (LOD) of 7 ng/mL for morphine in phosphate-buffered saline (PBS, pH 7.4) solutions, well below the required clinical detection limit, and an LOD of 6 ng/mL for fentanyl in PBS, close to the clinical requirement. The sensor can selectively detect fentanyl from a mixture of morphine and fentanyl and be regenerated in 2 min with up to 93.66% recovery rate after five cycles. The efficacy of our sensor is further validated in artificial interstitial fluid and human urine samples.