According to a family statement released by NASA, Cernan, a retired naval officer, died following ongoing health issues.
"It is with very deep sadness that we share the loss of our beloved husband and father," the family said.
"Our family is heartbroken, of course, and we truly appreciate everyone's thoughts and prayers. Gene, as he was known by so many, was a loving husband, father, grandfather, brother and friend," the statement added.
"Even at the age of 82, Gene was passionate about sharing his desire to see the continued human exploration of space and encouraged our nation's leaders and young people to not let him remain the last man to walk on the moon."
- 'Ad Astra' -
The space community quickly took to Twitter to pay tribute to Cernan and honor his legacy.
"Saddened by the loss of pioneer, fellow naval aviator, astronaut and friend Gene Cernan #RIP #lastmanonthemoon," said retired American astronaut Scott Kelly.
"Ad Astra, Gene," tweeted NASA's Kennedy Space Center, using a Latin phrase meaning "to the stars."
"We mourn the loss of our friend Gene Cernan, the Last Man on the Moon and a hero for the ages," said the Smithsonian National Air and Space Museum. "Godspeed the Commander of Apollo 17."
On what would be the last manned mission to the lunar surface, Cernan's second to the moon, the crew captured the iconic image of a full view of the planet Earth dubbed "Blue Marble."
"Everything's three dimension when you look back at the Earth in all its splendor, in all its glory, multicolors of the blues of the oceans and whites of the snow and the clouds," the astronaut said of his final mission, in a 2007 interview with NASA.
The footprints Cernan left on the moon's surface remain visible more than four decades later.
"I'd just like to record that America's challenge of today has forged man's destiny of tomorrow," he said as he left the moon for the final time.
- 'Bold ambitions' -
Born in Chicago in 1934, Cernan received a degree in electrical engineering from Indiana's Purdue University in 1956.
He went on to earn a master's degree in aeronautical engineering from the US Naval Postgraduate School in California.
Cernan was one of a class of 14 astronauts chosen to join NASA in 1963, and went on to serve on both Gemini and Apollo missions.
He has spent 566 hours and 15 minutes in space -- logging more than 73 hours on the moon's surface.
Cernan retired from the Navy and NASA in 1976. He later entered the private business sector and provided television commentary during early space shuttle flights.
"The Last Man on the Moon" -- a documentary about his life -- was released in 2016.
The moonwalker's death comes one month after that of another space legend -- John Glenn, the first American to orbit the Earth.
In December, Glenn was the last of the first seven US astronauts who led the nascent 1959 US space program to pass away.
Cernan's death marks the latest from a generation of space pioneers whose ranks are dwindling.
"Truly, America has lost a patriot and pioneer who helped shape our country's bold ambitions to do things that humankind has never before achieved," said NASA administrator Charles Bolden of Cernan's death.
Cernan is survived by his wife Jan, one daughter, two step-daughters and nine grandchildren, the family said.