In mammals, the A Disintegrin-like And Metalloproteinase domain with Thrombospondin type 1 motifs (ADAMTS) family comprises 19 secreted proteases, including 6 members with the ability to cleave large aggregating proteoglycans: ADAMTS1, 4, 5, 9, 15, and 20. ADAMTS9 has an essential, non-redundant role during embryogenesis, as Adamts9 null embryos die prior to completing gastrulation and Adamts9 haploinsufficiency results in cardiovascular and ocular anomalies. ADAMTS9 proteolytic activity is required for proteostasis of versican, a widely distributed large aggregating proteoglycan/hyalectan in the provisional extracellular matrix present during early development. Despite its importance, ADAMTS9 proteoglycanase activity has not been directly compared to that of ADAMTS1, 4, and 5, due to difficulties in expressing and purifying the >200 kDa full-length form of ADAMTS9. Like ADAMTS1, 4, and 5, ADAMTS9 cleaves versican V1 isoform at the Glu441-Ala442 site, but unlike them, cleavages at other sites are unknown. Here, we expressed a truncated ADAMTS9 variant (ADAMTS9 MDTCS) consisting of all ADAMTS ‘core domains’ that render it more comparable in size and domain structure to ADAMTS1, 4, and 5 and compared its activity against versican, aggrecan and the small leucine-rich proteoglycan biglycan. A catalytically inactive ADAMTS9 MDTCS variant (ADAMTS9 EQ) was used as the control in all experiments. We identified cleavage sites in versican (V1 and V2 isoforms) and biglycan by all 4 ADAMTS family members using a quantitative label-free proteomics strategy. Moreover, using a quantitative substrate cleavage assay, we established that ADAMTS9 MDTCS versicanase activity at the Glu441-Ala442 site is 175-fold lower than ADAMTS5, 9-fold lower than ADAMTS4, and 5.5-fold higher lower than ADAMTS1. These provide systematic analysis of the proteoglycanase activity in the ADAMTS family and highlight differences and similarities in cleavage site specificities that could potentially be leveraged to design selective small molecule inhibitors for therapeutic applications.