How nervous systems evolved is a central question in biology. An increasing diversity of synaptic proteins is thought to play a central role in the formation of specific synapses leading to nervous system complexity. The largest animal genes, often spanning millions of base pairs, are known to be enriched for expression in neurons at synapses and are frequently mutated or misregulated in neurological disorders and diseases. While many of these genes have been studied independently in the context of nervous system evolution and disease, general principles underlying their parallel evolution remain unknown. To investigate this, we directly compared orthologous gene sizes across eukaryotes. By comparing relative gene sizes within organisms, we identified a distinct class of large genes with origins predating the diversification of animals and in many cases the emergence of dedicated neuronal cell types. We traced this class of ancient large genes through evolution and found orthologs of the large synaptic genes driving the immense complexity of metazoan nervous systems, including in humans and cephalopods. Moreover, we found that while these genes are evolving under strong purifying selection as demonstrated by low dN/dS scores, they have simultaneously grown larger and gained the most isoforms in animals. This work provides a new lens through which to view this distinctive class of large and multi-isoform genes and demonstrates how intrinsic genomic properties, such as gene length, can provide flexibility in molecular evolution and allow groups of genes and their host organisms to evolve toward complexity.