The Las Vegas room opened in 1999 inside Mandalay Bay at the south end of the Strip, with the Blues Brothers cutting the ribbon. The music hall holds about 1,800 and is one of nine spaces on the site, from a members' club to a Southern restaurant; the chandelier over the floor came out of the original MGM Grand.

House of Blues is an American chain of live music concert halls and restaurants. It was founded by Isaac Tigrett, the co-founder of Hard Rock Cafe, and Dan Aykroyd, co-writer and co-star of the 1980 film The Blues Brothers. The first location opened at Harvard Square in Cambridge, Massachusetts, on November 26, 1992 (Thanksgiving Day). The chain has been a division of Live Nation Entertainment since July 2006, and there are 11 locations throughout the United States as of 2025.

The first House of Blues opened on November 26, 1992, in the Harvard Square commercial district and retail area of Cambridge, Massachusetts, as a live music concert hall and restaurant. The company was financed by Dan Aykroyd, Aerosmith, Paul Shaffer, River Phoenix, Jim Belushi, John Candy, and Harvard University, among others. This location closed in 2003 as the company sought a larger Boston venue. However, the hands-in-concrete driveway where members of the Blues Brothers and others left their mark, remains. Aykroyd is still associated with the brand and attends most openings, performing as one half of The Blues Brothers. In 1993 House of Blues launched a 501(c)(3) non-profit called International House of Blues Foundation which provided arts programs, resources and musical instruments for youths. The Music Forward Foundation continues to provide services for youth and has generated more than $20 million of support for these programs over its 20+ year existence. Also in 1993, the syndicated program The House of Blues Radio Hour launched in partnership with CBS Radio Hour. The show is hosted by Aykroyd, in character as Elwood Blues, and focuses on the history of blues music and the contemporary artists honoring the art form. Its final episode aired in July 2017. In 2024 The House of Blues Radio Hour was acquired by the U.S. Library of Congress.