Anti-Mormon sentiment was building and Hamblin and his family received their share. At that time he met and married Rachel Judd as his second (that is, plural) wife. His families moved west with the Mormons. He settled in Tooele Valley and became acquainted with local Indians who knew him as a friend. In 1854 Hamblin was called as a missionary to the Indians in southern Utah.

Again, he became known for his influence with Native Americans because of his integrity and his willingness to be friends with them. He had many spiritual experiences that caused the Indians to consider him invested with godly powers. After serving in his Indian mission for more than a year, Hamblin moved his family from Tooele to what is now Santa Clara. He then became president of the southern Utah Indian mission.

In the fall of 1857 Hamblin went north to confer with Brigham Young in Salt Lake City. On the way he encountered the Fancher Party of emigrants, California bound from Arkansas and Missouri. They asked him about the road and places to camp. He directed them to Mountain Meadows on the old Spanish Trail, about three miles from his home. He later expressed horror and repugnance at news of the massacre of the Fancher Party at Mountain Meadows. His wife Rachel helped care for the massacre survivors at the ranch.