It has been a long time coming for Romney, who failed in his bid for the nomination in 2008.
"I accept your nomination for president," Romney said in his prime-time speech.
"Now is the time to restore the promise of America," Romney declared to a nation struggling with 8.3 percent unemployment and the slowest economic recovery in decades.
"I wish President Obama had succeeded because I want America to succeed," he said. "But his promises gave way to disappointment and division."
TRANSCRIPT: Read the full text of Mitt Romney's GOP convention speech.Romney choked up at least twice, including when he recalled how he and wife Ann would awake to find "a pile of kids asleep in our room."
He was unstinting in his criticism of President Barack Obama, his Democratic quarry in a close and uncertain race for the White House, and drew cheers when he vowed to repeal Obama's signature health care law.
"This president can tell us it was someone else's fault. This president can tell us that the next four years he'll get it right. But this president cannot tell us that you are better off today than when he took office," Romney declared.
Clint Eastwood, legendary Hollywood tough guy, put the case for ousting Obama plainly moments before Romney made his entrance. "When somebody does not do the job, you've got to let `em go," he said to the cheers of thousands in the packed convention hall.
Romney's remarks came on a night when other speakers filled out a week-long portrait of the GOP nominee as a man of family and faith, savior of the 2002 Winter Olympics, savvy and successful in business, yet careful with a buck. A portion of the convention stage was rebuilt overnight so he would appear surrounded by delegates rather than speaking from a distance, an attempt to soften his image as a sometimes-stiff and distant candidate.
The latest polls show the race for the White House is very close, making Romney's speech even more important as he reaches out to the undecided.
On Wednesday night, Romney's choice for vice president, Congressman Paul Ryan, had Republicans on their feet.
"The work ahead will be hard. These times demand the best of all of us - all of us - but we can do this," said Ryan.
Ryan had no trouble convincing Republicans in Tampa, Fla., but many Americans are still unfamiliar with the congressman from Wisconsin. The 42-year-old has a reputation for tackling tough fiscal issues, including hot button topics like Medicare.
Ryan attacked the Obama administration for avoiding the tough decisions facing the country and for burdening young Americans with more debt.
"Obamacare comes to more than 2,000 pages of rules, mandates, taxes, fees and fines that have no place in a free country," said Ryan. "College graduates should not have to live out their 20s in their childhood bedrooms staring up at fading Obama posters and wondering when they can move out and get going with life."
TRANSCRIPT: Read the full text of Mitt Romney's GOP convention speech.There was a brief disruption during Ryan's speech on the convention floor. One woman was removed after interrupting him and calling for more funding for health care and birth control for women.
Also praising the Republican ticket on Wednesday were former Secretary of State Condoleeza Rice and Arizona Sen. John McCain, who beat Romney for the nomination in 2008, only to lose to President Barack Obama in the general election.
Look for ongoing reports from David Ono at the Republican National Convention in Tampa, Fla. Eyewitness News will also be at the Democratic National Convention in Charlotte, N.C., in September.
The Associated Press contributed to this report.
