The first settlement of any kind in Umatilla county was the Catholic Mission, established on the Umatilla above Pendleton, by Bishop A. M. A. Blanchet, Father J. B. A. Brouillet and Mr. Leclaire, November 27, 1847, two days before the Whitman massacre. This was the actual founding, but for several months previous they had been living at Fort Walla Walla, and negotiating with the Cayuses for land upon which to build the mission. After the horrible massacre at Wailatpu, they were unable to do any missionary work; and January 2, 1848, Bishop Blanchet left for Vancouver with Peter S. Ogden and the rescued prisoners. Father Brouillet and Mr. Leclaire remained at Umitilla, in accordance with a promise made to the Cayuses to stay with them as long as they and the Americans did not go to war. On the nineteenth of February 1848, the Cayuses went out to fight Oregon volunteers, and the next day Father Brouillet and his companion went to Fort Walla Walla, and about three weeks later to Willamette Valley. The Indians being displeased, burned their house and destroyed the property left behind them. This ended the first settlement in Umatilla County.

 The first actual American settler was Dr. William C. McKay, son of the celebrated Tom McKay, and grandson of Alexander McKay who came to Oregon in 1811 as a partner of John Jacob Astor, and perished soon after in the massacre of the Tonquin's crew at Vancouver Island. Dr. McKay was born and reared in Oregon, and it was his familiarity with, and confidence in this region that led him to make a settlement. After this difficulty with the Cayuse tribe had been adjusted a few Americans, and Hudson's Bay Company French, came to this section to locate. The majority of them selected choice spots on the Walla Walla, Touchet, Tukannon, and Mill Creek, while Dr. McKay located on the Umatilla River at the mouth of Houtama, or McKay creek. This was in the fall of 1851. The French settlers were chiefly in the Walla Walla valley, and not more than one or two, if any, were within the limits of Umatilla County. The great respect and regard entertained by the Cayuses for Tom McKay had, in a great measure, been conferred upon his son, and Dr. McKay was welcomed by them and received favors that would have been denied other Americans. He was looked upon as a Hudson's Bay Co. man, though he was born in Oregon, educated in New York, and had always identified himself with the Americans. This fact saved his life and that of several others a few years later. In 1851 an Indian agency was established on Umatilla, opposite the present town of Echo, by Dr. Anson Dart, Superindent of Indian affairs for Oregon. E. Wampole was installed as agent, and was succeeded the next year by Thomas K. Williams, and he by R. R. Thompson. The last named gentleman resided at the Dalles, and placed Green Arnold as his deputy at the agency. This station was known as Utilla, and in August 1851, a post office by that name was established there, being on the route between, Dalles and Salt Lake. A. F. Rogger was appointed postmaster. These were the only settlements in 1855 when the Indian war drove all Americans from the country east of the Cascades.

 In common with scores of others, Dr. McKay visited the Colville mines in the summer of 1855. His property was left in charge of Jones E. Whitney, who had came with his wife in the emigration of 1854 and had lived with the Doctor for a year as his partner. In the fall he started on his return from Colville, accompanied by Victor Trevitt, now living at the Dalles, and two Hudson's Bay French. They were several times stopped by Indians, but Dr. McKay represented Trevitt as a clerk of the Hudson's Bay Co., and they were not interfered with. When they reached the settlement of Brooke, Bumford and Noble, at Wailatpu, it was deserted, and while wondering at it, Howlish Wampo head chief of the Cayuses, rode up and informed them that the Americans had all gone to the Dalles, but that some people were up the river.  They proceeded up the river where they found a number of French settlers, among whom were Mr. Pambrun, Mr. McBean and a Catholic priest. Next morning the chief sent his brother with McKay and Trevitt as an escort, the two Frenchmen remaining at the camp. The Dr. found his place deserted by Whitney and his wife, the house door broken in, his property destroyed and his cattle gone. They remained there two days and had a big talk with the Cayuses, who were very sore about the sale of their land. They did not go to war as a tribe, but many of the young warriors joined the hostiles. Umhowlish, Stikas and others advised them to leave at once, as the feeling against Americans was so bad it was unsafe even for McKay to remain. They therefore departed for the Dalles as secretly as possible, passing the deserted agency as they went. McKay's place and the agency were both destroyed, and thus ended the second settlement of Umatilla County.