Prentice, the 58-year-old former MP and Conservative cabinet minister under Prime Minister Stephen Harper, handily defeated Wildrose candidate Kathy Macdonald in Calgary-Foothills.
"We heard Albertans loud and clear," Prentice told cheering supporters.
"Albertans want a lot more action and a lot less talk. They want a lot less politics and a lot more good government."
He cited the struggles ahead including the eroding price of oil and the continued struggles to get pipelines built from the oilsands to the coasts.
"Working on balancing these dual challenges begins tomorrow morning ... in earnest," said Prentice. "We're on the right path, but we know that the work has just begun."
In the other races, Health Minister Stephen Mandel scored a convincing victory over NDP candidate Bob Turner and Tim Grover of the Opposition Wildrose party in Edmonton-Whitemud.
In Calgary-Elbow, Education Minister Gordon Dirks edged out rivals John Fletcher of the Wildrose party and Greg Clark, leader of the Alberta Party.
In Calgary-West, PC candidate Mike Ellis, a Calgary police sergeant, held on to defeat Wildrose candidate Sheila Taylor in the tightest race of the night.
Wildrose Leader Danielle Smith told volunteers she was disappointed in the outcome, but tried to put a positive spin on the results.
"Tonight I believe a message has been sent," said Smith. "Albertans have told the PCs that they're willing to give them one last chance, but certainly not a blank cheque.
"I look forward to each of our candidates taking another shot at this in the general (election)."
Prentice called the byelections a month ago after winning the party's leadership race to replace former premier Alison Redford.
Prentice asked voters to focus on the changes he has made aimed at restoring public trust following the Redford era.
Redford resigned as premier earlier this year amid revelations she used taxpayer money to fund lavish travel and office perks for her and her inner circle.
It was a bitter campaign, particularly around Dirks, a former pastor and one-time head of the Calgary Board of Education.
Appointed to the portfolio by Prentice, Dirks had been accused by opponents of abusing his cabinet position to aid himself in the Calgary-Elbow race.
Last week, it was revealed Dirks ordered up two modular classrooms for a school in the constituency, leapfrogging other schools deemed a higher priority.
Dirks had also been photographed turning sod for future schools that have yet to find a builder.
Dirks, 67, told cheering supporters: "This is a deeply humbling moment for me. My heart is very, very touched tonight.
"We won because we have policies that resonate with Albertans."
Edmonton-Whitemud was the longtime riding of former PC cabinet minister and premier Dave Hancock.
Mandel successfully leveraged his name recognition as the former mayor of Edmonton, but it wasn't an easy campaign.
He dealt with public anger over lack of care beds for seniors, bottlenecks in emergency wards, and cancelled surgeries.
He told supporters he will continue the work he has started as health minister.
"Working with doctors, nurses, pharmacists, people in the industry, will allow us to find out the answers," said Mandel, 69. "Not answers from the top, but answers from working with people. That's what will make the difference in the coming months."
Hancock took Edmonton-Whitemud with 60 per cent of the votes in the 2012 general election. Mandel bristled when asked if he was concerned that his 42 per cent was a message from voters.
"This is a byelection and byelections are usually much more difficult and I think we did remarkably well," he said. "We got over 42 per cent of the vote, so, I'm not — silly question."
In Calgary-West, the Wildrose party had high hopes for Taylor, a former trustee and chair of the Calgary Board of Education. The former oil executive resigned her seat with the board earlier this month when she signed up to run.
She attacked Dirks on the modular classroom issue after her loss.
"What we saw from Mr. Dirks just in the last week was a case where he put his own personal interest ahead of the interests of Calgary students," she said.
The byelection outcomes don't have the potential to change the balance of power.
With the four byelections wins the Tories hold 61 seats in the 87-seat legislature — the same number they won in the last general election in April 2012.
The Wildrose have 17 seats, the Liberals five and the NDP four.
A general election is mandated by law to be held in the spring of 2016.
— With files from Bill Graveland and Lauren Krugel in Calgary and Rob Drinkwater in Edmonton.
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