Acid sphingomyelinases (aSMases) are enzymes involved in the repair of the plasma membrane in eukaryotic cells. However, little is known about their evolution. One relevant aspect of these enzymes is that, even though they show no homology at the sequence level, they are highly conserved structurally, and the catalytic domain in these enzymes seems to be unequivocally identical in enzymes with a wide range of activity, suggesting an evolutionarily conserved 'core' even in the absence of sequence homology. Here, we found that, despite lacking significant sequence identity, these proteins exhibit highly conserved overall protein architecture, specifically at the active site. Using a diffusive model based on multiple sequence alignment, the most probable predicted structure contains the helix/sheet structure found in the active site. Additionally, the aSMase domain is found in proteins with no apparent functional relevance to the specific aSMase enzymatic activity, suggesting that this domain is widespread in eukaryotic organisms. Based on previous research and the findings presented here, we hypothesize that the aSMase domain has broader implications for protein function beyond sphingomyelin metabolism and that, in protists, these enzymes diverged more in terms of enzymatic regulation, with several orthologs expressed in the same cell. The data presented here suggest that aSMases may incorporate domains that function as protein scaffolds for yet-to-be-determined protein interaction networks and functions. Further experimental research may elucidate the functional roles and evolutionary origins of aSMases across diverse organisms and identify novel therapeutic targets in parasites.