Reeve, who was 52, fell into a coma Saturday after going into cardiac arrest while at his suburban New York home and died Sunday at a local hospital.
Reeve was being treated at Northern Westchester Hospital for a pressure wound that he developed, a common complication for people living with paralysis. In the past week, the wound had become severely infected, resulting in a serious systemic infection.
Reeve's wife, actress Dana Morosini Reeve, issued a statement thanking "the millions of fans from around the world who have supported and loved my husband over the years." His mother, Barbara Johnson, told the syndicated TV show "The Insider": "I'm glad that he is free of all those tubes."
"The world has lost a tremendous activist and artist, and an inspiration for people worldwide. I have lost a great friend," said actor and comedian Robin Williams, whose friendship with Reeve dated back to the days when they were both students at the Juilliard School of Performing Arts.
Reeve broke his neck in May 1995 when he was thrown from his horse during an equestrian competition in Culpeper, Va., and at first fought a mighty battle with depression and suicidal feelings.
But with the help of friends and loved ones, Reeve emerged from his personal tragedy an even more remarkable person - a story he told in his best-selling autobiography, "Still Me" - and became a powerful lobbyist for medical research, especially on behalf of fellow sufferers of spinal cord injuries.
Enduring months of therapy to allow him to breathe for longer and longer periods without a respirator, Reeve founded the Christopher Reeve Paralysis Foundation and began to use his show biz contacts and accumulated good will to push for change.
Reeve was active in his support for stem cell research, lobbied Congress for better insurance protection against catastrophic injury, and moved an Academy Award audience to tears with a call for more films about social issues.
"Hollywood needs to do more," he said in the March 1996 Oscar awards appearance. "Let's continue to take risks. Let's tackle the issues. In many ways our film community can do it better than anyone else. There is no challenge, artistic or otherwise, that we can't meet."
Reeve's support of stem cell research helped it emerge as a major campaign issue between President Bush and Sen. John Kerry. His name was even mentioned by Kerry earlier this month during the second presidential debate.
He returned to directing and acting in a 1998 production of "Rear Window," a modern update of the Hitchcock thriller about a man in a wheelchair who becomes convinced a neighbor has been murdered. Reeve won a Screen Actors Guild award for best actor in a television movie or miniseries.
Reeve was generous in sharing his thoughts on how to live a full life no matter what the challenge, and two years ago, published another book - "Nothing Is Impossible: Reflections on a New Life" - with meditations on that subject.
Reeve was born Sept. 25, 1952, in New York City, son of a novelist and a newspaper reporter. He was around 10 when he made his first stage appearance in Gilbert and Sullivan's "The Yeoman of the Guard" at McCarter Theater in Princeton, New Jersey.
He starred in virtually all of the theatrical productions at the exclusive Princeton Day School. By age 16, he had joined the actors' union.
After graduating from Cornell University in 1974, he landed a part as coldhearted bigamist Ben Harper on the television soap opera "Love of Life." He also performed frequently on stage, winning his first Broadway role as the grandson of a character played by Katharine Hepburn in "A Matter of Gravity."
Reeve's first movie role was a minor one in the submarine disaster movie "Gray Lady Down," released in 1978. "Superman" soon followed. Reeve was selected for the title role from among about 200 aspirants. With his 6'-4" frame and steely blue eyes, Reeve was a perfect fit, reports CBS News Correspondent Kelly Cobiella.
Though he owed his fame to it, Reeve made a concerted effort to, as he often put it, "escape the cape." He played an embittered, crippled Vietnam veteran in the 1980 Broadway play "Fifth of July," a lovestruck time-traveler in the 1980 movie "Somewhere in Time," and an aspiring playwright in the 1982 suspense thriller "Deathtrap."
More recent films included John Carpenter's "Village of the Damned," and the HBO movies "Above Suspicion" and "In the Gloaming," which he directed. Among his other film credits are "The Remains of the Day," "The Aviator," and "Morning Glory."
Recently, Reeve returned to the comic-book story that made him famous. He made several guest appearances on the WB series "Smallville" as Dr. Swann, a scientist who gave the teenage Clark Kent insight into his future as Superman.
"He was just tireless. It was just unbelievable to witness," said Al Gough, an executive producer of "Smallville."
His last project as a director, "The Brooke Ellison Story," is set to premiere October 25 on A&E Television. Based on the book "Miracles Happen: One Mother, One Daughter, One Journey," it tells the true story of a girl who became a quadriplegic at age 11 but pushed ahead despite her disability and graduated from Harvard University.
Active in many sports, Reeve owned several horses and competed in equestrian events regularly. Witnesses to the May 1995 accident said Reeve's horse had cleared two of 15 fences during the jumping event and stopped abruptly at the third, flinging the actor headlong to the ground. Doctors said he fractured the top two vertebrae in his neck and damaged his spinal cord.
Reeve tried many therapies throughout his life, and had others move the legs he could not - so the muscles would be ready when he would be able to use them once more. He never gave up on his goal of walking again, despite missing his target of doing so by age 50.
His condition did however improve in ways that were remarkable to the medical community. In 2000, Reeve was able to move his index finger, and a specialized workout regimen has made his legs and arms stronger. He had also regained sensation in other parts of his body.
One experimental procedure placed electrodes in Reeve's diaphragm to allow him to breathe on his own for up to 15 minutes.
"I think he was only the third person to have this done, " People magazine senior editor Jess Cagle told the CBS News Early Show.
"You really believed that Chris Reeve was going to walk again," Cagle said. "He kept promising us that."
While filming "Superman" in London, Reeve met modeling agency co-founder Gae Exton, and the two began a relationship that lasted several years. The couple had two sons - Matthew, 25, and Alexandra, 21 - but they never married.
In 1992, Reeve married Dana Morosini; they had one son, Will, 12. His wife became his frequent spokeswoman after the accident.