A senior-level source with direct knowledge of the situation told ABC News that Trump asked Price for his resignation.
In a letter to Trump, Price wrote that he regretted that "recent events have created a distraction" from the administration's objectives, and that he was resigning in order for the president "to move forward without further disruption."
"Secretary of Health and Human Services Thomas Price offered his resignation earlier today and the president accepted," read a statement from White House press secretary Sarah Sanders, adding that Trump intends to designate Don Wright, the current deputy assistant secretary for health and director of the Office of Disease Prevention and Health Promotion as acting secretary.
The revelation about Price's trips drew widespread criticism from Democrats and an investigation was launched last week by the HHS Office of Inspector General. Price took as many as 26 private flights and flew on military planes on trips to Europe and Africa at an estimated cost to taxpayers of over $1 million, according to Politico.
Earlier in the day, Trump teased a decision on Price's status to reporters, saying would decide by the end of the day whether he might fire the secretary. He repeated that he was "not happy" about the secretary's travel, a position he first shared Wednesday.
On Thursday, Price expressed regret over his trips and pledged to reimburse the government for his portion of the cost of the chartered jets. A HHS spokesperson declined to comment in the wake of the resignation on whether the former secretary still intended to follow through on the promise.
A source with knowledge of Price's intentions earlier said that he would pay $51,887.31 for the flights, just a fraction of the over $400,000 that the chartered flights were said to have cost. Military flights to Africa, Asia and Europe, on which Price was joined by his wife, pushed the total over the $1 million figure, according to Politico.
The resignation comes three days after Senate Republicans announced they would not hold a vote this week on the party's latest attempt to repeal and replace the Affordable Care Act, the Graham-Cassidy bill. Price played an integral role in promoting the administration's thus far unsuccessful efforts to roll back the Democratic health care legislation passed under the Obama administration.
Last Friday, the HHS Office of Inspector General confirmed its inquiry into Price's flights, noting it was focused "on whether the travel complied with Federal Travel Regulations, but may encompass other issues related to the travel."
"We take this matter very seriously, and when questions arose about potentially inappropriate travel, we immediately began assessing the issue," read a statement from the office.
After last week's report, a collection of congressional Democrats authored a letter to the inspector general requesting an investigation. The Department of Health and Human Services maintained that Price "used charter aircraft for official business in order to accommodate his demanding schedule."
During his short tenure leading HHS and during his time in Congress, Price gained a reputation as an outspoken critic of government excess. In 2009, while still serving in the House, Price characterized a proposal to spend $550 million of government planes for government officials and members of Congress as "fiscal irresponsibility."
Prior to his nomination by Trump in November to join the Cabinet, Price served six terms as the U.S. representative of Georgia's 6th Congressional District, rising to the chairmanship of the House Budget Committee in 2015. Prior to his political career, Price worked as an orthopedic surgeon.
He was narrowly confirmed as secretary by a 52-47 margin in February.
ABC News' John Santucci and Justin Fishel contributed to this report.