And after nearly three full months into the year, he now has to face a head-on a challenge that is likely to haunt his tenure as speaker for the foreseeable future: seemingly irreconcilable differences among his fellow Republicans.
"Moving from an opposition party to a governing party comes with growing pains," Ryan told reporters Friday. "And well, we're feeling those growing pains today."
The stunning setback was particularly excruciating for the 47-year-old, who made his name in Washington as a conservative policy wonk committed to repealing the Affordable Care Act and ascended to the powerful position of House speaker in fall 2015.
The bill that too many of his fellow colleagues ultimately rejected was based on Ryan's signature policy agenda, called "A Better Way."
"I don't know what else to say other than Obamacare is the law of the land. It'll remain law of the land until it's replaced," he said. "We're going to be living with Obamacre for the foreseeable future."
It's a rough reminder that life is different for Ryan now than before Trump was elected. During the Obama administration, the Republican-controlled House could pass message bills that would repeal Obamacare with impunity, knowing they would die in the Senate or be vetoed by the President.
"This is how governing works when you're in the majority. We need to get 216 people to agree with each other to write legislation. Not 210. Not 215," Ryan said at Friday's press conference. "We were close but we didn't have 216 people. That's how legislating works."
Even before the decision to pull the health care bill, Republican lawmakers were worried about the impact of a potential defeat.
New York Rep. Chris Collins said Friday afternoon prior to the cancellation of the vote that if the health care bill fails, it would leave a "black eye" on his party's ability to legislate.
"If we don't pass this, I personally don't think we pass a 2018 budget. We couldn't pass a 2017 budget. So if we couldn't pass a 2017 budget and this happens today, how are we going to pass a 2018 budget?" he said.
"And that's the vehicle for tax reform. And if you don't do tax reform, where does the money come from for infrastructure? That's how critical this vote is today."
But both Trump and Ryan say they plan to go to tax reform next.
Ryan spoke alone from behind the podium, and he was not flanked by any of the Republican colleagues or White House officials who had furiously worked with him for weeks to try to get the health care legislation through the House.
And while questions are being raised about Ryan's relationship with Trump, the two have publicly insisted that they have a healthy dialogue.
The Wisconsin Republican said he had directly informed Trump that he did not have the votes
, and that the President accepted his recommendation that Republicans yank the bill.
Trump publicly blamed Democrats -- not the speaker -- for Friday's failure.
"I like Speaker Ryan. He worked very hard," Trump said from the Oval Office.
But it will take more than platitudes to unite his party, especially after both conservative and moderate factions demonstrated their strength this week.
The GOP's internal divisions were Ryan's gravest challenge, and one he never came close to resolving.
Members of the conservative Freedom Caucus refused to get behind the bill, referring to leadership's proposal as "Obamacare Lite" that simply didn't go far enough in gutting the law.
But when Ryan and his deputies attempted to appease that faction by offering to go further than their original bill in gutting Obamacare, that only irked the more moderate lawmakers in the House conference.
In the final days, Ryan worked around the clock to try to bridge the two factions, holding back-to-back meetings and one-on-one sessions. But the differences could not be reconciled.
"We came really close today, but we came up short," Ryan said at a news conference. "I will not sugarcoat this. This is a disappointing day for us."