The name "St. Lucie" is originally derived from the name of a settlement near Jupiter Inlet which was founded in 1566 on St. Lucia Day, a Christian feast day that commemorates Lucia of Syracuse, an early-4th-century virgin martyr. After "La Florida" and "St. Augustine," it is the oldest place name in the United States.

First settled in 1891, Spruce Bluff consisted of a community of several families with a school, post office, sawmill, and pineapple plantation. The land the settlement was located on is now part of the Spruce Bluff Preserve in Port St. Lucie. Along with an old cemetery near the old settlement, the preserve also contains a prehistoric Indian mound that was built by the Ais Indians who lived in this area some 2,000 years ago.

Apparently the city planners didn't have access to spellcheck because there are numerous Port St. Lucie streets with misspelled names, including (among many others) Twylite Terrace, Granduer Avenue, Calender Street, Amethist Terrace, and Lama Avenue.

It might seem strange that there are no ports in Port St. Lucie, but the city was created by General Development Corporation, whose first major community, Port Charlotte, was established on the Gulf Coast in the 1950s. It then became GDC policy to include "Port" in the names of all the developments it planned, including Port Malabar, Port St. John, Port LaBelle, and North Port.

When GDC asked the state legislature to incorporate 70 miles of uninhabited land into Port St. Lucie, it purposely omitted the developed lands, which would have included 250 homes in the River Park area. To include them would have required approval by the residents that already lived there, which wasn't likely. So House Bill No. 953, introduced by State Representative Rupert Smith and signed April 27, 1961, by Gov. Bryant Farris, made Port St. Lucie a city without any residents.

In Moonraker (1979), 007 is pursued by the forces of Hugo Drax as he travels up the Amazon River looking for a secret research facility. Naturally, Bond has all sorts of gadgets on his boat to thwart his pursuers. For this famous chase scene, the North Fork of the St. Lucie River doubled as the Amazon.

The New York Mets have trained at Clover Park in Port St. Lucie since it opened in 1988. Park on the right-field side of the ballpark and you'll see a sign warning you to stay away from the swampland because of alligators. Port St. Lucie is also home to the St. Lucie Mets Minor League Team and all the New York Mets Minor League operations.

Vanilla Ice, best known for the 90s rap hit "Ice Ice Baby", acknowledged in 2004 that the wallaroo (a cross between a wallaby and a kangaroo) and goat found wandering the streets of Port St. Lucie had escaped from his backyard. After paying a fine for an expired permit, he was allowed to reclaim them.

The Devil's Tree in quiet Oak Hammock Park is tied to one of Florida's first serial killers, a deputy sheriff who murdered two teenage girls in 1973 and buried them beneath this oak tree, which has a knot on its trunk in the shape of a goat's head with horns. There have been several attempts to cut or burn the tree down, but every attempt has failed, even after Catholic priests attempted an exorcism. Locals have countless stories of strange activity after nightfall and warn visitors to stay away. Fortunately, the park has a strict curfew at sunset.

In 2012, Mayor JoAnn Faiella received several emails from Cai Xuchang, mayor of Wuxing, China, requesting to be a sister city. Wuxing is in the north of east China's coastal Zhejiang Province and is east of Shanghai. With a population of 591,800, the city has nine towns and seven urban communities. Today, Port St. Lucie and Wuxing are "sister cities" under Sister Cities International, a program that connects U.S. and other international cities in an effort to boost economic development.