St. Brendan first opened along Western Avenue between Second and Third Streets in the year 1915, staffed by the Sisters of the Immaculate Heart. In 1927, the Sisters of Charity of the Blessed Virgin Mary (BVMs) replaced the Sisters of the Immaculate Heart. In 1988, the administration of the school was assumed by a Sister of Saint Joseph of Carondelet and that continued until June 2018. Since 1988, the charism of the Sisters of Saint Joseph of Carondelet—Unity and Reconciliation—has permeated the school through the spirit of the documents and traditions, as well as the day-to-day operations.
In 1960, the school building on Western Avenue was demolished because of safety concerns, and a new school building was constructed on the opposite side of the school yard facing Manhattan Place. This main building currently houses homerooms for 1st through 8th grades, as well as the main office, staff work rooms, computer lab, and library.
In 2009, construction was completed on two additional buildings surrounding a grass sports field and paved space for parking and student drop-off and pickup. One new building houses a spacious kindergarten classroom, a science lab and art room, an updated faculty lounge, a learning resource room, and two multipurpose conference rooms. The second building houses the Parish Center, with the capabilities to be used as a gym and an auditorium.
Since construction finished in 2009, St. Brendan has undergone more changes, including the installation of SMART Boards in every classroom, improvement of the speed and function of the wireless network, and a complete update of the computer lab. In 2013, the grass sports field was renamed the Gus Deppe Memorial Field in honor of Gus, a beloved member of the class of 2015.