The departures reduce the party's standing in the 51-seat legislature to five seats.
Gordie Gosse, a former house speaker, is leaving for health reasons, while house leader Frank Corbett said in a statement he wants to pursue other interests.
Gosse gave an emotional speech to the legislature, telling the house he needs time to fully recover after surgery for throat cancer last May.
"I don't want this to be a sad day, I want this to be a happy day," he said. "I have to look after my health."
Gosse was accompanied by his wife Sue, who watched from the public gallery as members from all parties rose in applause. He reflected on his nearly 12 years in politics and his humble beginnings.
"It's been a pleasure to be here as an MLA," he said. "You know I grew up in a company house and to come from there to here — what a journey."
Corbett wasn't at the legislature on Thursday, but after 17 years as a member he said he wants to take on other pursuits and spend more time with his family.
NDP Leader Maureen MacDonald told the legislature she has mixed emotions and "had been dreading this moment."
Corbett's absence reflected his desire to avoid attention, she added.
"It is very much like Frank not to want the flowery tributes and the emotional features that go with these kinds of tributes. That's just not Frank Corbett."
Corbett served as deputy premier and minister of the public service, labour and advanced education after the NDP won government for the first time in the province's history in 2009.
Premier Stephen McNeil joined in the tributes, telling the legislature that Gosse represented the "the kind of people that should be in this place."
MacDonald said her caucus will feel the loss of a combined 29 years worth of political experience.
"I would be lying if I didn't admit that it's a hit to the caucus," she said.
The resignations follow the recent death of Liberal member Allan Rowe, leaving three seats vacant.
McNeil has up to a year to call byelections but he said his preference would be to have the seats filled by the time the house sits in the fall.
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