The Wisconsin congressman, speaking before a fervent crowd, lambasted President Obama for "shifting blame" and "throwing away money" before speaking earnestly about the need to face the nation's tough issues through "good-faith reforms and solutions."
"I'm the newcomer to the campaign, so let me share a first impression. I have never seen opponents so silent about their record, and so desperate to keep their power," he said. "Ladies and gentlemen, these past four years we have suffered no shortage of words in the White House. What's missing is leadership in the White House. And the story that Barack Obama does tell, forever shifting blame to the last administration, is getting old. The man assumed office almost four years ago - isn't it about time he assumed responsibility?"
Watch Paul Ryan's full speech at the Republican National Convention below:
After launching into an attack of Mr. Obama's health care plan, Ryan's speech was interrupted by a protestor, who shouted "my body, my choice!" and held up a bright pink sign reading "VAGINA" before being escorted by security.
"Behind every small business, there's a story worth knowing," he said. "A lot of heart goes into each one. And if small businesspeople say they made it on their own, all they are saying is that nobody else worked seven days a week in their place."
Hitting on a Republican refrain that's become ubiquitous in recent weeks, he added: "Yes, you did build that."
Defending his controversial Medicare overhaul, which would transform the nation's popular entitlement system into a voucher system, Ryan embraced impending debate over the issue.
"In this election, on this issue, the usual posturing on the left isn't going to work. Mitt Romney and I know the difference between protecting a program, and raiding it," he argued. "Ladies and gentlemen, our nation needs this debate. We want this debate. We will win this debate."
(Watch: The 2012 Republican presidential primary, in four minutes.)
Despite the obvious distinctions between himself and Romney - Ryan pointed out their differences in faith, career paths, and taste in music - the vice presidential hopeful stressed commonalities in "the things that matter."
"A generation apart," he said. "That makes us different, but not in any of the things that matter."
"The right that makes all the difference now, is the right to choose our own leaders. And you are entitled to the clearest possible choice, because the time for choosing is drawing near," he said. "So here is our pledge. We will not duck the tough issues, we will lead. We will not spend four years blaming others, we will take responsibility.
We will not try to replace our founding principles, we will reapply our founding principles."
"The work ahead will be hard," he added. "These times demand the best of us - all of us, but we can do this. Together, we can do this."