Thursday's industrial action comes more than a month after the NSW Nurses and Midwives' Association first voted in favour of statewide action that subsequently saw demonstrations at 150 public hospitals.
"Patients play Lotto depending which day they go to hospital," union General Secretary Brett Holmes told AAP.
"They (patients) could get lucky and get a properly staffed shift or they could get unlucky.
"So our members ... want to see a better health system that will guarantee that there are enough nurses ... to look after patients."
Nurses are demanding a nurse-to-patient ratio of one-to-four on hospital wards and a midwife-to-patient ratio of one-to-three, as well as a 4.75 per cent pay rise versus the 2.5 per cent a year allowed by the state government.
Mr Holmes said the government had not extended an offer to the union since its last meeting with Premier Dominic Perrottet, who has been on two and a half weeks' paternity leave since March 17.
Following the February strike - which was the first by NSW nurses in a decade - Mr Perrottet said he hoped "we can provide a resolution" but noted the issues were complex.
He also said Health Minister Brad Hazzard was in "constant dialogue" with the union.
Nurses from up to 170 hospitals will take part in a series of rallies on Thursday in Sydney, Albury, Bathurst, Broken Hill, Dubbo, Goulburn, Newcastle, Orange, Port Macquarie, Wagga Wagga, Wollongong and other areas.
They will also protest outside Parliament House, where the NSW Greens will on Thursday introduce a bill to the upper house to legislate the union's preferred nurse-to-patient ratios.
"Nurses and midwives are at breaking point," Greens health spokeswoman Cate Faehrmann said.
"It's time for the government to listen to their calls for safe nurse-to-patient ratios so that patients get a safe level of care."
Ms Faehrmann noted Queensland and Victoria had already legislated nurse-to-patient ratios and South Australia was considering the issue.
The union said life-preserving services will be maintained at all public hospitals throughout the day.
The NSW government had successfully argued to the industrial relations umpire the strike should not go ahead, but the union has defied the decision.
The latest strike comes after some NSW paramedics took industrial action on Tuesday with similar demands for improved resources and staffing.
On Monday, the paramedics union shared photos of ambulances queuing outside hospitals including Royal Prince Alfred, Wollongong, Wyong, John Hunter, Concord and others, waiting to offload patients at emergency departments.