In the winter of 1803-1804, Meriwether Lewis and William Clark set up their winter headquarters at Camp DuBois at the mouth of the Wood River in preparation for their expedition of discovery near where present day Wood River is located. Their arrival foreshadowed the arrival of the pioneers beginning to move westward after the Revolutionary War. Until this time the area had been inhabited mainly by Native Americans and fur trappers.

While many towns sprung up in the region during the 19th century, the Wood River valley was largely empty except for railroad tracks and a few scattered farm houses. The arrival of the Standard Oil Refinery in 1907 changed all that. The main products of the first refinery were kerosene, fuel oil, coke, paraffin and asphalt. By 1911 the company began making gasoline to meet the demand caused by the popularity of the automobile. Workers began to flood into the area to work at the refinery and in 1907, A. E. Benbow, a local entrepreneur, founded Benbow City, a wide open town of saloons, gambling and brothels. The City of Wood River was incorporated in 1908 and developed around Benbow City. Wood River and East Wood River merged in 1911 and annexed Benbow City in 1917.

In the 1920's, Wood River was the one of the fastest growing communities in the country and had more workers than houses. To solve this problem Standard Oil bought and built many Sears and Roebuck catalog homes which can be seen throughout the community. A concentration of "Honor Built" homes can be found on the east side of the 100 and 200 blocks of 9th Street. Directly south of Wood River is the small town of Roxana, sometimes referred to as "The town that Shell built," and visitors interested in the history of the refineries can visit the Shell History Museum (formerly known as the Wood River Refinery Museum) which is located on Route 111. 

Today, Wood River is a well-developed community with small businesses, schools, and churches. The town is proud of its heritage and the Wood River Heritage Council is continuously developing sites of historical significance and of interest to visitors. The Wood River Museum and Visitors Center welcomes visitors and tells the story of the town. A replica of Camp DuBois is located near the intersection of Routes 143 and 3 near the mouth of the Wood River and every May the town celebrates the French fur trapping era and the Lewis and Clark spirit at the Camp DuBois Rendezvous at this site.