There is increasing demand for anti-doping drug monitoring in sports and food safety checks by developing sensitive and fast analytical methods. Here we report the development of hybrid Ir/SiNW as a new MALDI matrix for the detection of small molecules. This matrix is characterized by sufficient UV absorption, low-noise background, and high efficiency in ionization of small molecules. Sensitive detection of clenbuterol (LOD: 0.18 pmol) and a variety of other small molecules has been achieved using the Ir/SiNW matrix with a reproducible performance. Compared to the individual components separately, the matrix of hybrid Ir/SiNW synthesized via in situ growth can promote the MS signal intensity by up to 10 fold under identical experimental conditions. We provide a unique mechanism for the high performance of the hybrid Ir/SiNW matrix with the characteristic properties of hydrogen atom transfer and enhanced protonation at the interface of the hybrid nanostructures. Our approach of using a hybrid Ir/SiNW matrix enables detection of clenbuterol quantitatively in complicated biological samples and in vivo experiments, promising a useful tool for food security and anti-doping drug monitoring in sports.