Before there was a provincial hospital in Chanthaburi, medical services were provided by the primary health clinic with Luang Narindr Prasatwetch (Jen Suntarothai), the public health official of Chanthaburi, being the first resident doctor. The original location was on Tha Luang Road, Mueang District, Chanthaburi Province, which has since been demolished and replaced with the Chanthaburi College of Technology, Jewelry, and Gemology Department.

In 1937, Luang Narindr Prasatwetch, while serving as a Member of Parliament for Chanthaburi, coordinated with the Public Health Department of the Ministry of Interior to establish a hospital in Chanthaburi. The selected location was Tainon Palad (or Nern Pa Rong Hai) on the road opposite Thung Na Choei, covering an area of approximately 77 rai 1 ngan 8 square wah (according to land deed number 5754, totaling 74 rai 20 square wah), with part of the land donated by local benefactors.

In 1965, the Cabinet approved the establishment of a nursing and midwifery school at Phra Pokklao Hospital. Queen Rambhai Barni laid the foundation stone on March 12, 1965, and the school opened in October 1965 with the first class of 20 students. In 1966, Queen Rambhai Barni became the patron of Phra Pokklao Hospital and its nursing and midwifery school, now known as Phra Pokklao Nursing College, Chanthaburi, under the Praboromarajchanok Institute, Office of the Permanent Secretary of the Ministry of Public Health.

In 1981, Dr. Chaisit Thanarakul, then director of the hospital, initiated a medical education project for rural students and requested permission to use public land for the construction of student, faculty, and staff housing, sports fields, water reservoirs, and a water supply system. This expansion was complemented by a land donation from Apai Janthawimol, adding 2 rai 3 ngan 90 square wah, connecting the hospital's territory.

By 1982, Phra Pokklao Hospital had grown to 560 beds and began receiving the first and second classes of medical students from Chulalongkorn University and the Ministry of Public Health's rural medical education project. On May 31, 1982, Dr. Sem Pringpuangkeo, the then Minister of Public Health, presided over the opening of the first clinical medical education center in Thailand.

Phra Pokklao Hospital received royal patronage from Princess Maha Chakri Sirindhorn, who named the emergency building "Thepprathan Building" and presided over its opening on April 25, 1994. She also inaugurated the King Prajadhipok statue on June 20, 2008, and made a private visit to the hospital on October 21, 2018.

Currently, Phra Pokklao Hospital is a 755-bed center hospital covering a total area of 246 rai 43 square wah. It provides comprehensive medical services with specialized physicians in various fields and houses several excellence centers, including the Heart Center, Cancer Center, Trauma Center, Neonatal Center, and Organ Transplant Center. As of 2024, the hospital is constructing additional parking facilities and modern surgical and obstetrics buildings to replace the old ones. Thanks to the royal patronage of King Prajadhipok and Queen Rambhai Barni and the dedicated efforts of the hospital staff, Phra Pokklao Hospital continues to advance with the goal of becoming a "modern hospital, a medical center of expertise in the East, trusted by patients and satisfying to staff."