<p>The ubiquitin-binding protein p62, encoded by <i>Sequestosome 1 (SQSTM1)</i>, is an essential molecular adaptor for selective autophagy. Heterozygous mutations deleting or disrupting the ubiquitin-associated (UBA) domain of p62 have been reported as the major genetic cause for Paget’s disease of bone (PDB), the second most common skeletal disease, characterized by hyperactive osteoclasts and focal increases of bone turnover. In this study, we aimed to determine the impact of a similar <i>sqstm1</i>/p62 mutation on the skeleton of zebrafish. We successfully established a <i>sqstm1</i>^{<i>tmΔUBA</i>} zebrafish line with premature truncation of the UBA domain and performed skeletal phenotyping of heterozygous and homozygous mutant zebrafish. Homozygous <i>sqstm1</i>^{<i>tmΔUBA</i>} zebrafish suffered from early lethality after 6 mpf, possibly related to a dysregulated autophagy process. Nevertheless, we detected skeletal abnormalities that were generally more severe in older animals and in homozygous versus heterozygous <i>sqstm1</i>^{<i>tmΔUBA</i>} zebrafish. MicroCT analysis and histologic staining showed alterations in the vertebral bodies and/or bone density in heterozygous <i>sqstm1</i>^{<i>tmΔUBA</i>} zebrafish. We also detected signs of osteocytic osteolysis in carriers of a mutant <i>sqstm1</i>^{<i>tmΔUBA</i>} allele, shown by a higher percentage of enlarged osteocyte lacunae at 12mpf (36% in heterozygote mutants, 20% in wild types). By performing scale histomorphometry, we also detected a higher degree of scale resorption in homozygous <i>sqstm1</i>^{<i>tmΔUBA</i>} zebrafish at 6 mpf. In conclusion, we have generated a <i>Sqstm1</i> mutant zebrafish model with features of PDB, characterized by focal bone defects and increased osteoclast activity. This model may be useful to further define PDB disease mechanisms and other p62-related (patho)physiological processes.</p>