Bishop Louis Walsh was appointed the fourth Bishop of the Diocese of Portland and consecrated at the Cathedral of the Immaculate Conception, October 18, 1906.

Louis S. Walsh, a native of Salem, Massachusetts, attended Holy Cross College for one year before furthering his studies in seminaries in Montreal, Paris and Rome. His first assignment as a priest was St. Joseph's Church in Boston's West End. In 1884, he was appointed Professor of Church History and Canon Law at the newly opened Saint John's Seminary in Brighton, Massachusetts.

In 1887, he became the first supervisor of Catholic schools for the Archdiocese of Boston, a post he held until his election as the fourth Bishop of Portland in 1906.

An important priority for Bishop Walsh was expanding Catholic education for young people. The Cathedral Girl's High School, based in the former Kavanagh School, and the Catholic Institute for Boys (which became Cheverus High School in 1925), located at 100 Free Street, were opened in 1909.

From 1918-1920, Bishop Walsh purchased land on State and Winter Streets, including Judge William Lebaron Putnam's house at 166 State Street, which he opened as the King's Academy for Girls and eventually served as the Monastery of the Precious Blood. Finally, in 1921, Bishop Walsh purchased land on Locust Street for the construction of a grammar school, which was home to Cathedral School.

During this time Bishop Walsh also instituted extensive renovations to both the Cathedral and the Chapel. In the Chapel a small organ was installed, as well as the stained glass windows that are there today. Stations of the Cross were also added, in addition to a magnificent marble baptismal font, modeled after one in Pietrasanta, Italy. The font was moved into the Cathedral during the Millennium Restoration.

In the Cathedral the most important additions were the exquisite Mayer of Munich stained glass windows. These are among the most beautiful in the world, and the Cathedral is one of the few that have all Mayer windows in it, including the clerestory windows over the nave.

The Cathedral's Golden Jubilee in 1919 saw additional refurbishing and redecorating in preparation for the October 12th Jubilee celebration.

In February 1924, Bishop Walsh went on a canonical visit to Rome and France. He returned to Portland exhausted from his trip and died a few days later on May 12th. Interment was in the Cathedral crypt, where Bishop Bacon is also buried.