The Old Globe Theatre opened for the California Pacific International Exposition on May 29, 1935, as a temporary structure that featured 50-minute versions of Shakespeare’s plays. After the success of the Exposition, local citizens raised $10,000 in 1936 to have the theater complex retrofitted as permanent structures. In February 1937, the State of California chartered the San Diego Community Theatre, a non-profit corporation, to coordinate fundraising and renovation activities for the theatre as well as to create a production company. The Community Theatre, which changed its name to the Old Globe Theatre in 1958, leased the land and buildings in Balboa Park from the City of San Diego, and continues to do so as of 2014. The renovated Old Globe Theatre opened on December 2, 1937 with John Van Druten's The Distaff Side. Aside from a six-year occupation by the U.S. Military during World War II, the theatre has operated continuously since its opening.

One of the original Distaff Side cast members was Craig Noel, who continued to act and direct at the Old Globe, eventually becoming its artistic leader in 1947. Noel’s vision shaped the Old Globe throughout his seventy-year career with the theatre. Noel and Board of Directors President Lowell Davies played instrumental roles in establishing the world-renowned Shakespeare Festival, which began in 1949 as a cooperative venture with San Diego State University, a partnership that ended after four seasons. Noel began employing professional Equity actors for the Shakespeare festivals in 1959, shifting the theatre to professional status. This transformation established the Old Globe as the oldest continuing professional not-for-profit theatre in California. The San Diego National Shakespeare Festival continued as an Old Globe solo venture until 1984. After a twenty-year hiatus, the theatre re-instituted the festival in 2004 and continues to produce summer Shakespeare productions annually.

Also through Craig Noel's efforts, Falstaff Tavern became a second stage in 1963. This arrangement proved successful, and in 1969 the Globe remodeled the Tavern and renamed it the Cassius Carter Centre Stage, in honor of the late San Diego arts patron and Shakespeare scholar. In addition, Noel created Globe Educational Tours, a touring company that introduced the fundamentals of theatre to disadvantaged K-12 students in San Diego schools through live performance and lesson plans; and the Play Discovery Program, which provided new playwrights the opportunity to develop their talents through manuscript evaluations and possible production by the Old Globe Theatre. Both programs began in 1974. Seven years later, in collaboration with Dr. Jorge Huerta, Noel established Teatro Meta, a bicultural program aimed at strengthening cultural understanding between Hispanic and Anglo communities through the production of plays written, performed, and directed by the Hispanic community.

Arson destroyed the Old Globe Theatre on March 8, 1978, but the Cassius Carter Centre Stage, offices, dressing rooms, scenery, and costume shops survived. To meet the need for the summer Shakespeare Festival, the Globe quickly erected an outdoor festival stage in only 52 days. The actual rebuilding of the Old Globe Theatre required an extensive fundraising effort and several years to complete. The new Old Globe opened on January 14, 1982.

In 1981, the board of directors established an artistic and administrative triumvirate to efficiently operate the new three-theatre complex. Craig Noel was named executive producer. Jack O'Brien, the nationally-acclaimed director who had staged eight productions at the Old Globe, became artistic director. Thomas Hall, who came to the Old Globe with extensive administrative and production experience, was named managing director.

Also in 1981, the theatre’s board of directors established the Old Globe as a year-round professional company, marking the beginning of an incredible growth period. In 1983, Jack O’Brien’s production of Thornton Wilder’s The Skin of Our Teeth became the first live theatre telecast on PBS. In 1984, the Old Globe broke the national record for the largest subscription base for any non-profit theatre, topping 40,000 subscriptions. In that same year, the Old Globe was awarded a Tony for Outstanding Achievement by a Regional Theatre.

The Old Globe’s winning streak ended abruptly in 1984 with the destruction of the festival theatre by another fire. The outdoor stage was rebuilt in 1985 and named the Lowell Davies Festival Theatre in honor of the Globe's board president from 1945-1976, who had organized the Globe 400, a group of patrons whose donations provided a scholarship fund to assist promising amateur actors.

The board of directors has been the governing body of the Old Globe Theatre since 1938. It creates institutional policies, establishes committees that shape the direction of the Old Globe, and controls funds. The Executive Committee, a sub-committee of the board of directors, has the power to make decisions on behalf of the board. Another organization significant to the Old Globe is the Globe Guilders, established in 1957 to raise funds and to promote membership and attendance at Old Globe productions.

The three-theater complex, which includes the Old Globe, the Cassius Carter Centre Stage (remodeled and renamed the Sheryl and Harvey White Theatre in 2009) and the Lowell Davies Festival Stage, is collectively named the Simon Edison Centre for the Performing Arts in honor of the late husband of Helen Edison, a generous donor to the Old Globe building fund. The Centre has a total seating capacity of 1,446, and is unique in that all theater production facilities and administration offices are located within the complex.

As of 2014, the Old Globe produces 15 mainstage productions yearly, incorporating all periods and styles. The Old Globe continues to honor its commitment to Shakespeare and other classic plays, while nurturing the development and production of new works. The Old Globe’s 2014 operating budget of approximately $20 million makes the theatre one of San Diego's largest arts institutions. Over 250,000 people annually attend Globe productions and participate in its educational and outreach services.