Cathepsins are enzymes capable of degrading proteins intracellularly. They occur ubiquitously in opisthokonts, but their potential to provide insight across the evolutionary transition from protists to metazoans remains poorly investigated. Here, we explore the evolution of cathepsins using comparative analyses of transcriptomic datasets, focusing on both, protists (closely related to metazoans), and early divergent animals (i.e., sponges). We retrieved DNA sequences of nine cathepsin types (B, C, D, F, H, L, O, Z, and silicatein) in the surveyed taxa. In choanoflagellates, only five types (B, C, L, O, Z) were identified, all of them being also found in sponges, indicating that while all cathepsins present in protists were conserved across metazoan lineages, cathepsins F and H (and probably D) are metazoan acquisitions. The phylogeny of cysteine protease cathepsins (excluding cathepsin D) revealed two major lineages: lineage B (cathepsins B and C) and lineage L (cathepsins F, H, L, O, Z). In the latter lineage, a mutation at the active site of cathepsin L gave rise to silicatein, an enzyme exclusively known to date from siliceous sponges and involved in the production of their silica spicules. However, we found that several sponges with siliceous spicules did not express silicatein genes and that, in contrast, several aspiculate sponges did contain silicatein genes. Our results suggest that the ability to silicify may have evolved independently within sponges, some of them losing this capacity secondarily. We also show that most phylogenies based on cathepsin and silicatein genes (except for that of cathepsin O) failed to recover the major lineages of sponges.