Multiple myeloma osteolytic disease is caused by an uncoupled bone-remodelling process with an increased osteoclast activity. Disease development relies on interactions between myeloma cells and bone marrow stromal cells. Recent findings suggest a role for glycan-binding proteins in myeloma microenvironment. Here, we investigated lectins involved in osteoclastogenesis and their role in myeloma bone disease. Microarray data analysis showed a lower expression of galectin-1 (gal-1) in mature osteoclasts compared to monocytic progenitor cells, confirmed at the RNA and protein levels in osteoclast cultures. Confocal microscopy showed that gal-1 localised predominantly in the sealing zone of mature osteoclasts. Although equal differentiated-osteoclast numbers, gal-1−/− osteoclasts showed a higher resorption activity compared to wild-type controls. Micro-computed tomography showed an aberrant bone phenotype with decreased bone densities in gal-1−/− mice. In vivo, tumour progression was faster in gal-1−/− mice and associated with a marked bone loss. Additionally, myeloma cells were found to decrease gal-1 expression in osteoclasts. Our results demonstrate that galectin-1 regulates osteoclast activity with an increased resorption by gal-1−/− osteoclasts and decreased bone densities in gal-1−/− mice. We observed an enhanced tumour development in gal-1−/− mice compared to wild-type mice, suggesting that galectin-1 has a functional role in stromal cells in myeloma microenvironment.