We report that cellulose nano-crystals (CNCs) can be used as a sensitive and selective layer in surface acoustic wave (SAW) sensors for in-situ HCl gas detection. CNCs were prepared through directly hydrolysis of cotton fiber and were spin-coated on quartz SAW resonators to form the sensitive layer. The CNCs have been identified to have abundant hydroxyl groups on their surfaces, which can act as the perfect adsorption sites for H2O, which can further act as the active sites for HCl gas adsorption. The absorption of HCl on the CNCs layer, thus leads to an increase of its mass, causing negative responses of the SAW sensors. Ambient humidity and thickness of CNCs layer are found to have significant influences on the responses of the SAW sensor. With an 80-nm-thick CNCs layer, the sensor shows a response of −2 kHz to 1 ppm HCl at 25 °C and relative humidity of 50% with an excellent selectivity and recovery characteristics.