Nociception and pain sensation are important neural processes in humans to avoid injury. Many proteins are involved in nociception and pain sensation in humans; however, the evolution of these proteins in animals is unknown. Here, we chose nociception- and pain-related proteins, including G protein-coupled receptors (GPCRs), ion channels (ICs), and neuropeptides (NPs), which are reportedly associated with nociception and pain in humans, and identified their homologs in various animals by BLAST, phylogenetic analysis and protein architecture comparison to reveal their evolution from protozoans to humans. We found that the homologs of transient receptor potential channel A 1 (TRPA1), TRAPM, acid-sensing IC (ASIC), and voltage-dependent calcium channel (VDCC) first appear in Porifera. Substance-P receptor 1 (TACR1) emerged from Coelenterata. Somatostatin receptor type 2 (SSTR2), TRPV1 and voltage-dependent sodium channels (VDSC) appear in Platyhelminthes. Calcitonin gene-related peptide receptor (CGRPR) was first identified in Nematoda. However, opioid receptors (OPRs) and most NPs were discovered only in vertebrates and exist from agnatha to humans. The results demonstrated that homologs of nociception and pain-related ICs exist from lower animal phyla to high animal phyla, and that most of the GPCRs originate from low to high phyla sequentially, whereas OPRs and NPs are newly evolved in vertebrates, which provides hints of the evolution of nociception and pain-related proteins in animals and humans.