But her cabinet will face multiple challenges, including restoring law and order, reconstructing parliament and the other key buildings that were attacked, reassuring the Gen Z protesters who want change - and others in Nepal who are fearful its young democracy and constitutional order could be derailed.
Another key task will be to bring those responsible for violence to justice.
Karki's appointment is a compromise resulting from talks that were brokered by Nepal's army chief this week. Elated Gen Z supporters are expressing their happiness on social media, and many see this as the next step in the new political course they want the country to take.
On Tuesday, Karki visited the protest site in Kathmandu where 19 people were killed in clashes with police the day before. She also met some of the injured who were being treated in hospital.
The new PM was born in a family with close contacts with the Koirala political dynasty, from the country's largest democratic party Nepali Congress, and later married the then-leader Durga Subedi.
She has said that her husband's support played a major role in her journey from a lawyer to Nepal's chief justice in 2016.
But Karki has not been free from controversy, hing faced an impeachment incident during her nearly 11-month tenure as chief justice.
Nepal's army is still patrolling the streets of Kathmandu as the country reels from its worst unrest in decades. Restrictions were only briefly lifted to allow residents to buy essential items.
The protests were triggered by the government's decision last week to ban 26 social media platforms, including WhatsApp, Instagram and Facebook - but they soon widened to embody much deeper discontent with Nepal's political elite.
In the weeks before the ban, a "nepo kid" campaign - spotlighting the lish lifestyles of politicians' children and allegations of corruption - had taken off on social media.
And while the social media ban was hastily lifted on Monday night, the protests had by that stage gained unstoppable momentum.