As one of the most prevalent diseases in the world, timely early intervention for periodontitis is a great challenge because the indicator is imperceptible. The exhaled H 2 S is considered to be a promising biomarker for fast and invasive periodontitis screening; however, the high-performance H 2 S gas sensor with excellent selectivity and sensitivity which is applicable to the oral cavity remains technically challenging. Herein, a self-assembled monolayer (SAM)-functionalized Au/In 2 O 3 nanofiber (NF) sensor for H 2 S exhalation analysis was developed to flexibly and effectively modulate the selectivity of the sensor. Through optimizing the specific binding capacity to H 2 S by systematic adjustment with terminal groups and alkyl chains of SAMs, the sensing performance of the SAM-functionalized Au/In 2 O 3 NF sensor is greatly enhanced. In the optimal (Au/In 2 O 3 -MPTES) sensor, the functionalization of the MPTES molecule could achieve significant response enhancement because of the stronger interaction between the sulfhydryl group at the end of the MPTES and H 2 S. Density functional theory simulation supports the proposed selective sensing mechanism via the analysis of adsorption energy and charge density distribution. The sensor exhibited a high response to H 2 S (1505.3-10 ppm) at an operating temperature of 100 °C with a low practical detection limit of 10 ppb and 13-145 fold enhanced selectivity. Furthermore, the Au/In 2 O 3 -MPTES sensor was successfully applied to distinguish the breath of healthy individuals and patients with severe periodontitis. This study provides novel design insights for the development of highly selective gas sensors for clinical aids in the diagnosis and detection of oral diseases such as periodontitis.