Spanning nine floors and 200,000 sq ft, the Wellington Place site can accommodate 3,000 people.
Its launch comes as part of a wider commitment from the Big Four firm to strengthen its regional offices and support local talent and businesses.
It follows a recent announcement of a £40m investment in an advanced research and engineering centre at Merchant Square, which is due to create 800 jobs over five years.
Kevin Ellis, chairman and senior partner at PwC, said: “We’re committed to playing a leading role in driving growth across the UK, helping to build a vibrant and sustainable economy.
“We see the commercial and societal benefits of basing our own operations across the country and Merchant Square is the latest in a number of offices we’ve opened in the last 18 months.”
The new office centres around hybrid working initiatives, with a wellbeing space accompanied by spaces that can be transformed from small meeting rooms for six people to large even areas for up to 150.
Moreover, booths in its restaurant come with screens to contact staff members who are working remotely.
Kevin MacAllister, regional market leader in Northern Ireland at the company, said: “This is an important step forward and signifies the confidence that PwC has in Northern Ireland, and our ambition for our clients and our people.
“As we look towards the future, we’re fully aware of the significance of opening a city centre office. Our people are what makes us the leading professional services firm and we know they value having a place to come together and collaborate.”
He added: “As we support them to do this safely, we’re also supporting the economy by bringing our workforce back into the city centre and helping local business recover.”