Phi Lambda Sigma was organized in March, 1965 on the campus of Auburn University, with the approval of the faculty of the School of Pharmacy. Following a two-year probationary period, the Auburn University Student Senate granted a charter to the Society on October 3, 1967. The Phi Lambda Sigma National Fraternity was legally incorporated in Lee County, Alabama on June 28, 1968. That same year, the name "Phi Lambda Sigma" was registered with the U.S. Bureau of Patents and Copyrights in the Washington D.C. and an official key was designed by the Balfour Company. The National Office was moved from Auburn University in 1992. In 1996, Phi Lambda Sigma contracted with the University of Tennessee College of Pharmacy for administration of the Society.

The Society encourages participation in all pharmacy activities. Since membership crosses fraternal and organizational lines, the Society does not compete with other pharmacy organizations.