"I feel like a million bucks. I think I'll do that again tomorrow," the 76-year-old Massachusetts Democrat was quoted by a family spokeswoman as telling his wife immediately afterward.
Dr. Allan Friedman, who performed the surgery at Duke University Medical Center, pronounced the operation a success and said it "accomplished our goals." Up next: chemotherapy and radiation, aimed at shrinking whatever is left of the tumor.
"The main goal is to remove as much of the tumor as possible to give any other therapy that we do a better chance of working," said Dr. John Sampson, associate deputy director of Duke's brain tumor center.
The sole surviving son of America's most glamorous and tragic political family was diagnosed last month with a malignant glioma, an often lethal type of brain tumor discovered in about 9,000 Americans a year.
Details about Kennedy's exact type of tumor have not been disclosed, but some cancer specialists said it might be a glioblastoma multiforme - an especially deadly and tough-to-remove type - because other kinds are more common in younger people.
Cutting a tumor down to size - or "debulking" it - is extremely delicate because of the risk of harming healthy brain tissue that governs movement and speech. But Friedman, who is the top neurosurgeon at Duke and an internationally known tumor surgeon, said Kennedy should not experience any permanent neurological effects.
Friedman said that Kennedy was awake during the entire procedure, reports CBS News correspondent Jeff Glor, which begins with opening the scalp and removing a piece of the skull to expose the brain. Sometimes, to avoid damaging areas that control speech, surgeons use a probe to stimulate parts of the brain, then hold a conversation with the patient.
"It doesn't hurt - -it's just this sort of uncomfortable awkward sort of thing," said CBS News contributing medical correspondent Dr. Sanjay Gupta. "But he can talk, he can carry on a conversation, identify flashcards, move his arm -- all important feedback for the surgeons."
In the following days, Kennedy will probably be given drugs to prevent brain swelling and seizures, which are possible complications of the surgery. The senator will also be closely watched for bleeding and blood clots, because strokes are also a risk, though they are uncommon. He is expected to return to Boston in about a week.
"After a brief recuperation, he will begin targeted radiation at Massachusetts General Hospital and chemotherapy treatment," Friedman said. "I hope that everyone will join us in praying for Sen. Kennedy to have an uneventful and robust recovery."
Doctors found the tumor last month after Kennedy suffered a seizure at his home on Cape Cod.
Rep. William Delahunt, D-Mass., a longtime friend of Kennedy's, said Kennedy threw himself into helping find treatment options in much the same way he searched for cures when son Edward Jr. faced bone cancer at age 12 and daughter Kara had lung cancer five years ago.
He went so far was to pull Kara out of Johns Hopkins and brought her to a Boston hospital when he was not satisfied with her initial course of treatment. In his own case, he met on Friday with family and doctors at Mass General and decided then to head to Duke for treatment, Delahunt said.
The outlook for patients with malignant gliomas is poor. Median survival for patients with moderately severe ones is three to five years, and less than a year those with the most severe type.
Surgery is rarely a cure but is considered the best option for extending life. But because of the risks, especially in someone as old as Kennedy, doctors sometimes advise against it.
In Friedman, Kennedy picked "one of the thought leaders" in the field of neuro-oncology, said Dr. Otis Brawley, the top doctor at the American Cancer Society. Dr. Matthew Ewend, chief of neurosurgery at the University of North Carolina, said: "He's an excellent surgeon. His patients are in very good hands."
Typical radiation treatment is five days a week for a month, using 3-D imaging techniques that narrowly deliver the beams to the tumor, affecting as little surrounding tissue as possible.
"After completing treatment, I look forward to returning to the United States Senate and to doing everything I can to help elect as our next president," Kennedy said is a statement issued before the surgery.
Monday's operation "spells nothing but hope," Duke's Sampson said from Chicago, where he was attending a conference of 30,000 cancer specialists. "What we're seeing with the surgery and this conference is that there's hope for patients with this kind of cancer."
Kennedy spoke on Sunday with Connecticut Democratic Sen. Christopher Dodd, one of his closest friends. But in his typical fighter's style, there was little talk about the cancer or his impending surgery. Instead, it was all about a pair of legislative measures - on mental health care and education - that Kennedy has been working on for months.
"He wants to get them done and he expects to be here when they are done," Dodd said. "He plans on coming back as soon as the doctors will let him."