Civilizations have existed in the proximity of the Indus River Valley regions of modern Pakistan and India from at least 3000 B.C. onward. Geographically, the region encompasses a swath of the Makran coast, the alluvial plain and delta of the Indus River, and the Runn of Kachchh. The regional tectonic setting is controlled by the collision of the Indian and Eurasian plates and the subduction of the Arabian plate beneath the Eurasian plate. Earthquakes have undoubtedly struck many ancient sites, but finding their footprint in a riparian environment represents a challenge for archaeoseismology. However, some insight into seismoarchaeological indicators can be gleaned from examining the earthquake effects produced by historical infrequent large-magnitude events that have occurred in the region. Studies of these earthquakes emphasize the importance of repeated reconstructions, direct faulting, river damming from seismic uplift, and coastal elevation change as indicators of past earthquakes. Examples of past earthquake effects are presented for Banbhore in the Indus Delta, Brahmanabad, and the Harappan sites of Kalibangan and Dholavira. Future hermeneutic investigations in the region need to incorporate a seismological/tectonic perspective and not rely solely on serendipity.