Amino acid substitution and insertions/deletions (indels) are two common events in protein evolution; however, current knowledge on indels is limited. In this study, we investigated the effects of indels on the flanking regions in protein structure superfamilies. Comprehensive analysis of structural classification of proteins superfamilies revealed that indels lead to a series of changes in the flanking regions, including the following: 1) structural shift in the tertiary structure, with a first-order exponential decay relation between structural shift and the distance to indels, 2) instability of the secondary structure elements in which parts of the α helix and β sheet are destroyed, and 3) an increase in the amino acid substitution rate of the primary structure and the nonsimilar amino acid substitution rate. In general, these quality changes are due to the combined effects of the "regional-inherent effect," "indel-accompanied effect," and "indel-following effect." Furthermore, these quality changes reflect changes in selective pressure. Indels are more likely to be preserved in regions with low selective pressure, and indels can further reduce the selective pressure on the flanking regions. These findings improve our understanding of the role of indels in protein evolution.