Pausch died at his home in Virginia, university spokeswoman Anne Watzman said. Pausch and his family moved there last fall to be closer to his wife's relatives.
Pausch was diagnosed with incurable pancreatic cancer in September 2006. His popular last lecture at Carnegie Mellon in September 2007 garnered international attention. Millions were moved to download the lecture and his subsequent book about life became a worldwide bestseller. And as he got sicker, his outlook seemed healthier, even as he faced the prospect of leaving his family, reports CBS News correspondent Richard Schlesinger.
During his Carnegie Mellon lecture, Pausch celebrated living the life he had always dreamed of instead of concentrating on impending death.
"The lecture was for my kids, but if others are finding value in it, that is wonderful," Pausch wrote on his Web site. "But rest assured; I'm hardly unique."
The book "The Last Lecture," written with Jeffrey Zaslow, leaped to the top of the nonfiction best-seller lists after its publication in April and remains there this week. Pausch said he dictated the book to Zaslow, a Wall Street Journal writer, by cell phone. The book deal was reported to be worth more than $6 million.
At Carnegie Mellon, he was a professor of computer science, human-computer interaction and design, and was recognized as a pioneer of virtual reality research. On campus, he became known for his flamboyance and showmanship as a teacher and mentor.
The speech last fall was part of a series Carnegie Mellon called "The Last Lecture," where professors were asked to think about what matters to them most and give a hypothetical final talk. The name of the lecture series was changed to "Journeys" before Pausch spoke, something he joked about in his lecture.
"I thought, damn, I finally nailed the venue and they renamed it," he said.
He told the packed auditorium he fulfilled almost all his childhood dreams - being in zero gravity, writing an article in the World Book Encyclopedia and working with the Walt Disney Co.
The one that eluded him? Playing in the National Football League.
To watch Randy Pausch's speech, click here
to read Steve Hartman's original report about Pausch's inspirational lecture
"If I don't seem as depressed or morose as I should be, sorry to disappoint you," Pausch said.
He then joked about his quirky hobby of winning stuffed animals at amusement parks - another of his childhood dreams - and how his mother introduced him to people to keep him humble: "This is my son, he's a doctor, but not the kind that helps people."
Pausch said he was embarrassed and flattered by the popularity of his message. Millions viewed the complete or abridged version of the lecture, titled "Really Achieving Your Childhood Dreams," online.
Pausch lobbied Congress for more federal funding for pancreatic cancer research and appeared on "Oprah" and other TV shows. In what he called "a truly magical experience," he was even invited to appear as an extra in the new "Star Trek" movie.
He had one line of dialogue, got to keep his costume and donated his $217.06 paycheck to charity.
Pausch blogged regularly about his medical treatment. On Feb. 15, exactly six months after he was told he had three to six months of healthy living left, Pausch posted a photo of himself to show he was "still alive & healthy."
"I rode my bike today; the cumulative effects of the chemotherapy are hurting my stamina some, but I bet I can still run a quarter mile faster than most Americans," he wrote.
Pausch gave one more lecture after his Carnegie Mellon appearance - in November at the University of Virginia, where he had taught from 1988 to 1997.
Pausch often emphasized the need to have fun.
"I mean I don't know how to not have fun. I'm dying and I'm having fun. And I'm going to keep having fun every day I have left. Because there's no other way to play it," he said in his Carnegie Mellon lecture. "You just have to decide if you're a Tigger or an Eeyore. I think I'm clear where I stand on the great Tigger/Eeyore debate. Never lose the childlike wonder. It's just too important. It's what drives us."
Born in 1960, Pausch received his bachelor's degree in computer science from Brown University and his Ph.D. from Carnegie Mellon.
He co-founded Carnegie Mellon's Entertainment Technology Center, a master's program for bringing artists and engineers together. The university named a footbridge in his honor. He also created an animation-based teaching program for high school and college students to have fun while learning computer programming.
In February, the Academy of Interactive Arts & Sciences in California announced the creation of the Dr. Randy Pausch Scholarship Fund for university students who pursue careers in game design, development and production.
He and his wife, Jai, had three children, Dylan, Logan and Chloe.
On a Web site detailing Pausch's progress with the cancer, the latest posting dated July 24 said Pausch had taken a downward turn and had entered a hospice program.
July 24: "A biopsy last week revealed that the cancer has progresed further than we had thought from recent PETscans. Since last week, Randy has also taken a step down and is much sicker than he had been. He's now enrolled in hospice. He's no longer able to post here so I'm a friend posting on his behalf because we know that many folks are watching this space for updates."
On June 26, Pausch posted his last update: "I continue to slowly recover.
"Chemotherapy has a cumulative effect, so it takes longer to recover the deeper one gets into this.
"Our current thinking is that more chemotherapy may not be wise; at this point, almost all potential chemotherapies may potentially make me so weak/sick that even if they were to slow the tumor, it would not be clear it would be the right tradeoff.
"We are currently narrowing down some immunuotherapy-based approaches that would presumably come with little or no side effects. More news as that proceeds."
In Sept., 2007, CBS News correspondent Steve Hartman reported on the outpouring of support that came after Pausch went public with his disease.