McCain thanked George Bush, the US president, "for leading us in those dark days following the worst attack on American soil in our history" in reference to the September 11 attacks in 2001.
While McCain stressed his credentials in crossing party lines in order to forge policy, he criticised Barack Obama, his Democratic rival in the US's November presidential election, for lack of experience, particularly in matters of foreign policy.
"I have that record and the scars to prove it. Senator Obama does not," he said to an ovation.
At one point in the speech, McCain appeared to be heckled by anti-war protesters, who were swiftly ejected from the Excel centre where the Republican National Convention has been held for the past four days.
McCain dismissed the protesters and told the audience not to listen to the "noise and static".
Outside the convention, police arrested 250 anti-war protesters after about 1,000 people tried to march on the centre, including several journalists, Reuters reported.
'Fight with me'
McCain also sparked huge applause when he thanked Sarah Palin, the governor of Alaska and his controversial vice-presidential running mate, and vowed to live up to his reputation as a "maverick" and get the Republican party "back to basics".
Follow McCain's speech live on Al Jazeera's Twitter service
"Let me offer an advance warning to the old, big spending, do nothing, me-first [and] country-second Washington crowd: change is coming," he said.
"I don't work for a party. I don't work for a special interest. I don't work for myself. I work for you."
The Arizona senator frequently drew on his own war experiences throughout the speech, recalling that his years spent as a prisoner-of-war in Vietnam led him to love his nation and to feel that "I will fight for her for as long as I draw breath".
"It's time for us to show the world again how Americans lead," he said.
Al Jazeera's Rob Reynolds in St Paul, Minnesota, said it was a pugnacious speech in which McCain invoked a fighting spirit, vowing at the end to "fight for what's right for our country" and calling on supporters to "fight with me".
On Iraq, McCain said he had fought for "the right strategy and more troops in Iraq", in reference to last year's so-called troop surge.
He praised General David Petraeus, the highest US general in Iraq, for implementing a strategy that "succeeded and rescued us from a defeat that would have demoralised our military, risked a wider war and threatened the security of all Americans".
McCain also condemned Iran as a "state sponsor of terrorism" and criticised Russia over Georgia, saying the US could not turn a blind eye "to aggression and international lawlessness that threatens the peace and stability of the world and ... the American people".
On domestic issues McCain vowed an end to dependence on foreign oil through drilling domestic oil wells, investing in nuclear and in "clean coal" technologies.
"We are going to stop sending $700 billion a year to countries that don't like us very much," he said to a standing ovation.
He also vowed to cut taxes, cut government spending and provide new jobs in a bid to shore up the US's ailing economy.
James Graff, the senior editor with Time magazine, told Al Jazeera that apart from evoking his military heritage, MCain's speech was "boring".
"The decks were loaded against him. It was directed more oustide the convention centre and that's why there were large swathes in that speech where you felt that people's attention was beginning to waiver.
"Palin was consolidating the base, McCain is trying to broaden it out and talk to the independents. I don't think his speech was as effective in that second intent as hers was in the first."
Barack Obama's campaign rejected the address as "more of the same" Republican policies that had already proven "disastrous".