Bone-resorbing osteoclasts mobilize proteolytic enzymes belonging to the matrix metalloproteinase (MMP) family to directly degrade type I collagen, the dominant extracellular matrix component of skeletal tissues. While searching for additional MMP substrates critical to bone resorption, Mmp9/Mmp14 double-knockout (DKO) osteoclasts—as well as MMP-inhibited human osteoclasts—unexpectedly display major changes in transcriptional programs in tandem with compromised RhoA activation, sealing zone formation and bone resorption. Further study revealed that osteoclast function is dependent on the ability of Mmp9 and Mmp14 to cooperatively proteolyze the β-galactoside–binding lectin, galectin-3, on the cell surface. Mass spectrometry identified the galectin-3 receptor as low-density lipoprotein-related protein-1 (Lrp1), whose targeting in DKO osteoclasts fully rescues RhoA activation, sealing zone formation and bone resorption. Together, these findings identify a previously unrecognized galectin-3/Lrp1 axis whose proteolytic regulation controls both the transcriptional programs and the intracellular signaling cascades critical to mouse as well as human osteoclast function.