Krabbe disease, also known as globoid-cell leukodystrophy (GLD), is a lysosomal storage disease (LSD) caused by the deficiency of the lysosomal enzyme β-galactocerebrosidase (GALC), resulting in severe neurological manifestations related to demyelination secondary to elevated galactosylsphingosine (psychosine) with its subsequent cytotoxicity. The only available treatment is hematopoietic stem cell transplantation that delays the disease onset but has not prevented further long-term neurological manifestations. Here, we report the identification of small molecules that enhance mutant GALC activity identified by quantitative cell-based high-throughput screen (qHTS). Using a specific neurologically relevant murine cell-line (145M-Twi) modified to express common human hGALC-G270D mutant, we were able to detect GALC activity in 1,536-well microplate format. The qHTS of approximately 46,000 compounds identified 3 small molecules that show significant enhancements of residual mutant GALC activity in primary cell lines from GLD patients. Interestingly, these compounds showed to increase the levels of GALC-G270D mutant in the lysosomal compartment. In kinetic assessments, these small molecules fail to disturb GALC kinetics profile at acidic conditions, which is highly desirable for folding-assisting molecules operating in the endoplasmic reticulum and not affecting GALC catalytic properties once in the lysosomal compartment. In addition, these small molecules rescue the decreased GALC activity at neutral pH and partially stabilize GALC at heat-denaturating conditions. These are drug-like compounds that can be used as the starting point to develop novel small molecule agents to treat the progressive neurodegenerative course of GLD.