Portland area civil engineer and museum enthusiast, J.C. Stevens, became a great supporter in the late 1930s, and was a driving force behind the museum’s reopening in 1946 at the Portland Hotel. Subsequent small exhibits occurred around town to generate interest and donations for a more permanent solution. In 1949, Ralph Lloyd hosted the temporary “Oregon Museum of Science and Industry” in his house on NE Hassalo Street, boasting the Northwest's first public planetarium and its 20-minute trip to the stars.

In 1951, OMSI sponsored the fossil expedition led by Lon and Berrie Hancock for young students to what later became the John Day Fossil Beds National Monument. From that first rustic tent camp, Hancock Field Station (Camp Hancock) has grown into a permanent camp facility that hosts 3,000 students, campers, and families each year through outdoor school and summer camp programs.

With annual attendance swelling to over 25,000 in 1955 and the house scheduled for demolition to make room for the new Lloyd Center, the City Council stepped forward to lease land in Washington Park to OMSI for the sum of one dollar per year. Students across Oregon raised funds for the projects and in the spirit of pioneer barn-raisings, over 400 volunteer union bricklayers laid 102,000 bricks in one day, and on June 7, 1958, the dream of a dedicated, hands-on science museum became a reality.

By the mid-1980's, OMSI's popularity surpassed the size of its facility six times over and a new group of community leaders began a $32M campaign to build a state-of-the-art science center, culminating with a milestone donation from longtime supporter, Portland General Electric, of an 18.5-acre site that held a historic sawdust-fired power generation plant. On October 24, 1992, the new 219,000 square-foot facilities opened, adding the USS Blueback, the last non-nuclear powered submarine built by the U.S. Navy, just two years later.

In 2014, a generous gift from John Gray enabled OMSI to purchase a 20-acre site in Newport to build The Coastal Discovery Center at Camp Gray. Opening to outdoor school and summer camp programming in 2016, Camp Gray hosts 5,000 students, campers, and families each year through outdoor school and summer camp programs.

In the years since, OMSI has continued to update science learning experiences and spaces at the museum and in its remote locations. Today, the museum serves over 1 million visitors at the museum and through education programs around the region. OMSI is ranked as one of the top science centers in the United States and has an international reputation for its innovative exhibits and educational programs.