Chitinase-3-like 1 (CHI3L1) protein is a secreted glycoprotein involved in various normal physiological processes, while its abnormal elevation is closely associated to carcinogenesis. CHI3L1 recruits and polarizes immune cells into the tumor microenvironment to maintain an immune suppressive environment, and directly stimulate cancer cells to promote their proliferation and migration. Recent studies demonstrated the feasibility of CHI3L1 deletion in cancer treatment on animal models, however, only a limited number of molecular modulators have been developed. To address this gap, a TRIC-based high-throughput screening (HTS) platform was developed, and a library of 5280 molecules was screened. From the screen, 11 hits (hit rate: 0.21 %) were identified as CHI3L1 binders, and 3 compounds (9N05, 11C19, and 3C13) were validated using surface plasmon resonance (SPR). Among them, 9N05 demonstrated the strongest binding affinity towards CHI3L1, and the K_d value was measured as 202.3 ± 76.6 μM. In summary, this proof-of-concept study demonstrates the feasibility of TRIC-based screening for CHI3L1-targeted molecules, and provide a potent tool for the future CHI3L1 molecular modulator development.