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Mr Ryan attacked the president for making cuts to the Medicare healthcare programme, but did not say that his own budget plan includes the same savings.
He complained that proposals by a budget commission were not adopted, but did not mention he opposed its report.
Thursday sees Mitt Romney formally accept the Republican nomination.
Mr Romney's speech to the convention is the challenger's biggest opportunity yet to make his case to the nation and is one of the set-piece events of the US election calendar.
He and Mr Ryan will challenge President Barack Obama and his Vice-President Joe Biden on election day, 6 November.
In a barnstorming speech to a rapt audience, Mr Ryan promised a "turnaround" for America and said Mr Obama's administration was tired and out of ideas.
The Wisconsin congressman said he and Mitt Romney would not duck the tough issues.
Mr Ryan, who serves as chairman of the House of Representatives Budget Committee, is known as a leading Washington policy "wonk", responsible for the budget plans backed by Mr Romney and Republicans in Congress.
But fact-checkers listening to his speech on Wednesday night quickly alleged that he had been slack with his facts.
On a key area of debate, the future of Medicare, the government-run health programme for over-65s, Mr Ryan accused the White House of slashing $716bn (£450bn) from the much-loved scheme.
But FactCheck.org, amongst others, said Mr Obama's 2010 healthcare reform law does not cut money from Medicare, but simply reduces the growth in spending on the scheme in an effort to keep it solvent.
In addition, Mr Ryan - who described the Obama plan as "the biggest, coldest, power play of all" - failed to note that he proposed virtually the same cuts in his own budget plans.
He accused the president of "political patronage" via his $800bn stimulus plan, passed in 2008. However, he neglected in his speech to mention that he sought to procure stimulus dollars for energy firms in his home state of Wisconsin, the Associated Press notes.
The vice-presidential hopeful was also accused of misleading his audience over the timing of the closure of a GM plant in his home town of Janesville, Wisconsin.
That statement earned Mr Ryan a "false" rating from PolitiFact.com, having failed to note that the plant closed under the previous administration of President George W Bush.
The Obama campaign released a web video on Thursday highlighting Mr Ryan's contentious statements, and dubbing him the "wrong choice for the middle class".
'We will lead'
Despite the arguments over Mr Ryan's choice of facts, his speech won a rousing reception from the audience in Tampa.
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The 42-year-old Wisconsin congressman, already a seven-term Washington veteran, is a hugely popular figure for many conservatives in the Republican fold because of his determination to take a hard line on fiscal issues facing the US.
Correspondents say the choice of Mr Ryan has made Mitt Romney's candidacy more palatable to conservatives who doubted his credentials during a long primary process.
He tore into the president on Wednesday night, accusing him of running out of ideas and waging a negative campaign.
"Fear and division are all they've got left," he said, adding: "Now all that's left is a presidency adrift, surviving on slogans that already seem tired, grasping at a moment that has already passed.
"We will not duck the tough issues - we will lead," Mr Ryan said. "We will not spend four years blaming others - we will take responsibility.
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"The work ahead will be hard. These times demand the best of us - all of us - but we can do this."
In one of the biggest applause lines of the night, Mr Ryan said: "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."
He pledged that a Romney-Ryan administration would create 12 million American jobs in its first term and cap federal spending at 20% of gross domestic product.
Speaking earlier, Senator McCain lambasted the Obama foreign policy, saying the president was not true to American values, and that he had abandoned Syria's people to a "savage and unfair fight".
"The demand for our leadership in the world has never been greater," the senator said. "People don't want less of America. They want more."
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Former Secretary of State Condoleezza Rice praised the Republican ticket in a speech that made no overt mention of President Obama.
"Mitt Romney and Paul Ryan will rebuild us at home and inspire us to lead abroad," she said. "They will provide an answer to the question, 'where does America stand?"'
President Obama's re-nomination will be confirmed next week at the Democratic National Convention in Charlotte, North Carolina.
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