He has millions of dollars in his campaign coffers, support from the Republican establishment and a tidal wave of national public opinion swinging in his favor. Recent statewide polls put him well ahead of his opponent, Christine O'Donnell.
But appearances can be deceiving, especially when the Tea Party Express throws its weight behind a primary challenger, as the case of felled Alaska Sen. Lisa Murkowski showed last month.
O'Donnell, a marketing consultant who ran unsuccessfully against Biden in 2008, is vowing to give Castle, a former governor and nine-term congressman, a run for his money, making the race the next big test for establishment Republicans who are trying to keep their jobs.
The Tea Party Express has spent $250,000 campaigning for O'Donnell so far, airing its first ad last week that cast O'Donnell as the more conservative candidate and Castle as "one of the most liberal Republicans in Congress."
Castle voted against the Recovery Act and Democrats' health care law, but he supported the 2008 bank bailout, cap-and-trade legislation and Democrats' campaign finance measure known as the Disclose Act. He also voted for the state fiscal aid bill last month.
A Tea Party Express poll of likely Republican voters last week showed O'Donnell and Castle in a dead heat.
But sources familiar with the Castle campaign say the veteran Republican has been prepared for the challenge in the wake of Murkowski's defeat and adopted a strategy that can win.
"I hear that Congressman Castle is not ignoring his opponent and has paid a lot of attention to what has happened this spring and is modeling his primary campaign after John McCain's primary campaign," Senate Minority Leader Mitch McConnell told ABC News' "Top Line" last week. "And I anticipate people [who do that will] have a better result."
With help from state and national Republican groups, the Castle campaign has gone on the offensive, raising allegations that O'Donnell faced home foreclosure, owed back taxes to the IRS and took 12 years to receive her college degree from Fairleigh Dickinson University because she didn't pay her tuition.
A Castle radio ad calls her "a financial disaster."
O'Donnell has largely denied the claims and accused Castle of employing "goons" to play dirty politics.
Tea Party Looks to Delaware
"As the Castle Campaign continues to sink in the polls, he is desperately digging up issues to distract voters from the fact that he voted with President Obama on just about every major spending bill this summer," O'Donnell wrote on her blog.
"Sad but true, his tactics have dominated a whole news cycle distracting some reporters from the real issues, like how we're going to get private sector jobs back in Delaware or why he voted for Cap and Trade."
Still, it's clear that at least part of the challenge facing O'Donnell is in getting her message out in the final days of the campaign. With only $20,000 in her war chest -- and $10,000 of debt -- she'll be unable to compete with the same intensity as Castle, who has $2.6 million in his accounts, according to the most recent Federal Election Commission filings.
And with recent independent polls showing Castle as having the greater chance of prevailing over Democratic county executive Chris Coons in the general election, Republican party leaders are eager to do whatever it takes to get Castle on the ballot.
"She is not a viable candidate for any office in the State of Delaware," state GOP party chairman Tom Ross told AP of O'Donnell. "She could not be elected dog catcher."
Former Republican Sen. Norm Coleman, who now runs a conservative political advocacy group, said, "Mike Castle is going to win his race in Delaware. ... It's just a personal observation from someone who hopefully knows a little bit about what is going on out there.
"But in this day and age, right now, there are a lot of surprises."
The potential for a surprise in Delaware has political strategists and party operatives on both sides watching closely. It's also keeping O'Donnell optimistic.
"My opponent has a sense of entitlement and assumes Delaware voters are just going to hand him a U.S. Senate seat," she said last week, "but I prefer to hand him a pink slip."