The endorsement comes just days before key contests in Ohio and Florida, and gives the Texas Republican momentum after winning Idaho on Tuesday and receiving the endorsement of former Republican candidate Carly Fiorina on Wednesday.
Lee was one of only three senators who missed today's Senate vote on a bill to aid those affected by opioid abuse. The other two were Sens. Rubio and Cruz.
While Cruz has become a divisive figure within the Republican conference in the Senate, Lee is considered one of his only allies, and at a recent campaign stop, Cruz said Lee was "someone I love like a brother."
But Lee had not endorsed until today, instead choosing to campaign for Cruz and Sen. Marco Rubio, a Republican from Florida.
"I've got two really good friends in this race," Lee told reporters at a Cruz campaign stop in South Carolina in February. "Any one of them running alone would have gotten my endorsement a long time ago."
The endorsement of Cruz over Rubio before Tuesday's primary in Rubio's home state of Florida may be a sign that Republicans see Cruz as the candidate who has the best chance to combat Donald Trump.
Rubio's campaign has failed to meet expectations in recent weeks, and the Florida senator was awarded zero delegates on Tuesday, when four states held contests in the Republican race for the nomination. While Rubio has the backing of 14 Senate Republicans, some of them publicly have expressed concern that he may need to exit the race if he fails to win Florida next week.
"I'm not going to give him any strategy or tell him what to do or what not to do, I'll let his people do that," Sen. Dean Heller (R-NV), who has endorsed Rubio, told reporters, "But I think he's going to have to really rethink moving forward after Florida."
"I think he has made the statement before that he needs to carry his state of Florida, and I agree with that," Rubio-backer Sen. Jim Inhofe (R-OK) said. "But I think most people would anticipate that that would be necessary for him to still be in the race."
This story originally appeared on NBCNews.com.