Around 150 public hospitals will be affected by the action from 7am on Tuesday with a skeleton staff working to ensure patient safety.
Thousands of nurses will rally outside NSW Parliament House to take their message to MPs as they return to Macquarie Street for the first sitting day of the year.
The strike is in defiance of an 11th hour ruling by the state's Industrial Relations Commission which on Monday ordered the union to refrain from any industrial action.
Health Minister Brad Hazzard met with the union on Monday in an attempt to avert the action over nurse-to-patient ratios and pay and says he's disappointed by the strike is proceeding.
"It's unfortunate ... there's been all sorts of efforts to try and work our way through their principal issues," he told Sydney radio 2GB on Tuesday.
NSW Nurses and Midwives Association General Secretary Brett Holmes says nurses have made the "difficult" decision to strike because they are stretched to the limit.
"They want significant change to occur and they need it to start happening now," he said.
"They are so angry about what they've experienced and their fear for the future is it's not going to get better without significant change."
Nurses want one nurse to every four patients on every shift and a pay increase above the government's prescribed public sector offer of 2.5 per cent.
Mr Holmes says any agreement would have to ensure "that nurses and midwives can go to work every day, knowing that there will be enough of them to deliver safe patient care".
Mr Hazzard agrees there needs to be enough nurses to ensure patients are safely cared for but says the union's demands would cost around $1 billion.
"I still need to be able to manage taxpayers' dollars and make sure it works," he said.
Nicole Richardson, a registered nurse and midwife who works at Gosford Hospital, on the Central Coast is joining the strike.
"It's inhumane what is expected of us," she said.
"We are not cuddling babies. We are trained, professional nurses and midwives trying to work in a broken system."
Premier Dominic Perrottet says the patient ratios the union wants aren't effective, and the system hadn't worked well in other states.
Some hospital workers, like those at Byron Central Hospital, support the strike but won't leave their nurses' stations over concerns they already don't have enough staff to provide the required care.
Liz McCall, a senior nurse at Byron Central and a union delegate, said the difficult work conditions had prompted many nurses to become politically active for the first time.
Many senior nurses had resigned or retired early during the COVID-19 pandemic because of their workloads, leaving a major gap in nursing experience.
"We can't provide the care we want to give - it's really scary," said Ms McCall, who has been a registered nurse for more than 40 years.