Smith, 58, lost two final appeals to the Supreme Court and one to a federal appeals court, arguing the execution was a cruel and unusual punishment.
In 2022, Alabama tried and failed to execute Smith by lethal injection.
He was convicted in 1989 of murdering a preacher's wife, Elizabeth Sennett, in a killing-for-hire.
According to the Death Penalty Information Center, Smith is the first person to be put to death using pure nitrogen gas anywhere in the world.
A journalist who witnessed the execution described to the BBC how he thrashed violently on the gurney, and said the process took around 25 minutes in total.
Elizabeth Sennett was killed in 1988
Alabama and two other US states have approved the use of nitrogen hypoxia as an alternative method of execution because the drugs used in lethal injections have become more difficult to find, contributing to a fall in the use of the death penalty nationally.
"Tonight Alabama causes humanity to take a step backwards," Smith said, according to witnesses. "Thank you for supporting me. Love all of you."
After the gas began to flow into his mask, the inmate is said to have smiled, nodded toward his family and signed "I love you".
One of the five members of the media transported to Holman Correctional Facility in Atmore to witness the execution told the BBC it was unlike any other he'd witnessed in Alabama.
"I've been to four previous executions and I've never seen a condemned inmate thrash in the way that Kenneth Smith reacted to the nitrogen gas," Lee Hedgepeth told the BBC.
"Kenny just began to gasp for air repeatedly and the execution took about 25 minutes total."
Breathing nitrogen without oxygen causes cells in the body to break down and leads to death.
Alabama Governor Kay Ivey, who did not respond to a request to attend the execution, confirmed Smith's death in a statement.
"After more than 30 years and attempt after attempt to game the system, Mr Smith has answered for his horrendous crimes," she said.
"I pray that Elizabeth Sennett's family can receive closure after all these years dealing with that great loss."