The first Lodge of Freemasons in the Mississippi territory was established by the Grand Lodge of Kentucky in Natchez on October 16, 1801. It was called Harmony Lodge. The second and third Lodges in Mississippi were chartered by the Grand Lodge of Tennessee. The first was chartered on August 2, 1816 and was also located in Natchez. It was named after Andrew Jackson. The second was chartered on April 19, 1817 in Port Gibson and was named after George Washington. In 1818, a year after Mississippi was admitted to the Union as the 20th state, these three Lodges, Harmony, Jackson and Washington formed the Grand Lodge of Mississippi.

In 1910, the Grand Lodge of Mississippi reorganized its Masonic home in Meridian to accommodate children and orphans of indigent Brothers. Eleven years later it opened a second home for boys in Columbus. By 1996, the homes were closed, but over its 88 years they cared for more than 1,000 children.

Today, Grand Master Bobby Ralph Ainsworth presides over 251 local Lodges and more than 21,000 brothers. The Grand Lodge supports many charities and local community projects.

Among the many honored members of the Grand Lodge of Mississippi include: US Senators John Stennis and Trent Lott, Governor William Winter and the Father of Country Music Jimmy Rogers.