According to oddsmakers, the odds are slightly against McGregor making history.
McGregor (19-2) has opened a plus-120 betting underdog to dos Anjos (25-7), who opened a minus-150 favorite. Lines were set by industry leader Nick Kalikas of MMAOddsBreaker.com.
UFC female bantamweight champion Holly Holm (10-0), who will attempt her first title defense against Miesha Tate (17-5) in the UFC 197 co-main event, has opened a significant 4-to-1 betting favorite. Tate is listed at plus-310.
"I originally opened the [McGregor] line on Dec. 20 and early action was on McGregor," Kalikas told ESPN.com. "The line has since settled at minus-130 for Dos Anjos.
"It's amazing what McGregor has accomplished, especially in his last fight against Jose Aldo, but dos Anjos has looked phenomenal for three straight fights by absolutely dominating three of the best lightweights in the world in Benson Henderson, Anthony Pettis and Donald Cerrone."
McGregor, who is 7-0 in the Octagon, has not fought in the 155-pound division since he signed with the UFC in 2013. Dos Anjos is riding a five-fight win streak, including a dominant five-round performance against Pettis in March that won him the belt.
A former boxing world champion, Holm goes from an 8-to-1 betting underdog in her most recent fight against Ronda Rousey at UFC 193 in November to a substantial 4-to-1 favorite.
The most Holm has been favored in a UFC contest was 5-to-1, in her promotional debut against Raquel Pennington in February.
"This is a classic striker versus grappler," Kalikas said. "Tate will want to wrestle while Holm will want to use her elite kickboxing skills. Tate has won four fights since losing her last UFC title shot and has showcased improved power on the feet, but Holm has proven to have great takedown defense and she should hold a significant edge in technique on the feet."
The UFC has not yet announced the two title fights on March 5, but sources have confirmed the matchups to ESPN. The event will take place in Las Vegas.