Originally named Clackamas District, it was one of the four original Oregon districts created by Oregon's Provisional Legislature on July 5, 1843, along with Twality (later Washington), Champooick (later Marion), and Yamhill. The four districts were redesignated as counties in 1845. At the time of its creation, Clackamas County covered portions of four present-day U.S. states and a Canadian province. The Columbia River became the northern boundary of the county in 1844. Soon after, John McLoughlin staked a land claim in Oregon City and built a house that in 2003 became a unit of the Fort Vancouver National Historic Site.

Most of the indigenous people of the Wil-lamet Valley were forcibly removed in February 1859, to the reservation of the Confederated Tribes of Grand Ronde. Most were moved without treaty or compensation for lost lands or resources. Some 22 tribes were moved during the cold winter. It is estimated that 30% did not survive the first year. The tribes eventually prospered, but outside of Clackamas County. They also never received any revenue or compensation from the logging of their homeland forests.

In addition, the Tribes of the Cascades Mountains were isolated to a Reservation after the signing of a treaty in 1859. Confederated Tribes of Warmsprings was established and remains a strong and vital player in actions that concern the Federal forests of the Cascades Range.

Oregon City was also the site of the only federal court west of the Rockies in 1849, when San Francisco, California, was platted. The plat was filed in 1850 in the first plat book of the first office of records on the West Coast and is still in Oregon City.

Around 1900, the spa and resort at Wilthoit Springs was a popular tourist destination. In 1902, the Willamette Meteorite was recovered from a field near present-day West Linn.

As of the 2010 census, there were 375,992 people, 145,790 households, and 100,866 families in the county. The population density was 201.0 inhabitants per square mile (77.6/km ). There were 156,945 housing units at an average density of 83.9 per square mile (32.4/km ). The racial makeup of the county was 88.2% white, 3.7% Asian, 0.8% American Indian, 0.8% black or African American, 0.2% Pacific islander, 3.1% from other races, and 3.2% from two or more races. Those of Hispanic or Latino origin made up 7.7% of the population. In terms of ancestry, 24.9% were German, 14.5% were English, 13.3% were Irish, 5.0% were Norwegian, and 4.9% were American.

Of the 145,790 households, 32.8% had children under the age of 18 living with them, 54.8% were married couples living together, 9.8% had a female householder with no husband present, 30.8% were non-families, and 24.1% of all households were made up of individuals. The average household size was 2.56 and the average family size was 3.04. The median age was 40.6 years.

The median income for a household in the county was $62,007 and the median income for a family was $74,905. Males had a median income of $53,488 versus $39,796 for females. The per capita income for the county was $31,785. About 6.1% of families and 9.0% of the population were below the poverty line, including 11.2% of those under age 18 and 6.2% of those age 65 or over.
As of the 2000 census, there were 338,391 people, 128,201 households, and 91,663 families in the county. The population density was 181 people per square mile (70 people/km ). There were 136,954 housing units at an average density of 73 units per square mile (28/km ). The racial makeup of the county was 91.27% White, 2.45% Asian, 0.71% Native American, 0.66% Black or African American, 0.17% Pacific Islander, 2.28% from other races, and 2.46% from two or more races. 4.95% of the population were Hispanic or Latino of any race. 20.7% were of German, 11.6% English, 9.1% Irish and 7.5% American ancestry.

There were 128,201 households, out of which 34.20% had children under the age of 18 living with them, 58.60% were married couples living together, 9.00% had a female householder with no husband present, and 28.50% were non-families. 22.00% of all households were made up of individuals, and 7.80% had someone living alone who was 65 years of age or older. The average household size was 2.62 and the average family size was 3.07.

The county population contained 26.20% under the age of 18, 8.00% from 18 to 24, 28.70% from 25 to 44, 26.00% from 45 to 64, and 11.10% who were 65 years of age or older. The median age was 38 years. For every 100 females, there were 97.50 males. For every 100 females age 18 and over, there were 94.90 males.

The median income for a household in the county was $52,080, and the median income for a family was $60,791. Males had a median income of $43,462 versus $30,891 for females. The per capita income for the county was $25,973. About 4.60% of families and 6.60% of the population were below the poverty line, including 7.60% of those under age 18 and 5.10% of those age 65 or over.

Since the county's creation, agriculture, timber, manufacturing, and commerce have been the principal economic activities. Mount Hood, the only year-round ski resort in the United States and the site of Timberline Lodge, is a major attraction for recreation and tourism, offering outdoor recreation activities from skiing and rafting to fishing and camping.