On March 9, 2020, after Abraham honored his pledge not to serve more than three terms, Letlow announced his candidacy.[10] Abraham publicly endorsed him concurrent with Letlow's announcement.[7] In the nonpartisan blanket primary on November 3, Letlow finished in first place with 33% of the vote, while State Representative Lance Harris, a fellow Republican, finished second with 17%.[11] Letlow won the December 5 runoff election with 62% of the vote.[12][13] The district is Louisiana's largest by area, covering most of 24 parishes, and includes Alexandria and Monroe, the population hubs, and Opelousas in Acadiana and Bogalusa in the Florida Parishes.[10]
Despite the COVID-19 pandemic, Letlow wore a mask only sporadically during his campaign, and was photographed speaking indoors to constituents when masks were not being worn by him or those gathered.[14] In October, he had encouraged Louisiana officials to relax pandemic restrictions, warning, "We're now at a place if we do not open our economy, we're in real danger."[14]
On December 18, 2020, Letlow announced that he had tested positive for COVID-19. He was hospitalized in Monroe.[15] After his condition deteriorated, he was transferred to the intensive care unit (ICU) of Ochsner LSU Health Shreveport on December 23.[16] On December 29, Letlow died from the virus at age 41.[4][15] The hospital reported that he had no underlying conditions when admitted but died in the ICU after suffering a "cardiac event" and could not be resuscitated.[17][18]
Louisiana Governor John Bel Edwards ordered flags in the state to be flown at half-staff on the day of Letlow's funeral.[17] He also scheduled the special election to fill Letlow's vacancy for March 20, 2021, with an April runoff if needed.[19] His widow Julia Letlow ran in the special election,[20] and won, avoiding a runoff.[21][22]
12WDSU Digital Team (December 30, 2020). "Congressman-elect Luke Letlow dies from COVID-19". WDSU. The following statement was issued by [Andrew] Bautsch: 'Congressman-elect Luke Letlow, 41, passed away this evening at Ochsner-LSU Health Shreveport due to complications from COVID-19.'