Columbia Independent School began in the fall of 1998, inspired by a group of families led by Justin Perry.

The families sought to provide a unique educational opportunity for the growing community in Columbia, Missouri.

Perry envisioned "a new independent, non-sectarian, academically challenging college preparatory school.

The students chose the lion, a symbol of strength, pride and leadership, and the colors blue and gold.

Students and teachers attended a three-day retreat at the YMCA Trout Lodge in southern Missouri before school began.

In April 2021, longtime community member and Director of Advancement and Operations Bridgid Kinney was named as interim Head of School.

In April 2008, CIS acquired the rights to a 62,000 sq ft (5,800 m2) building at 1801 N Stadium, Columbia, MO.

Currently, the new upper school addition, which is south of the original building, is scheduled to be complete in August 2024.

In spring 2016, the school began work on the Arts and Athletics Center, which added a stage and gymnasium.