Jessie Hoffman Jr, 46, was pronounced dead at 6:50pm on Tuesday at the Louisiana State Penitentiary, authorities said, adding the nitrogen gas had flowed for 19 minutes during what one official characterised as a "flawless" execution.
It was the fifth time nitrogen gas was used in the US after four executions by the same method — all in Alabama.
Three other executions, by lethal injection, are scheduled this week - in Arizona on Wednesday and in Florida and Oklahoma on Thursday.
Hoffman was convicted of the murder of Mary "Molly" Elliott, a 28-year-old advertising executive who was killed in New Orleans.
At the time of the crime, Hoffman was 18 and has since spent much of his adult life at the penitentiary in rural southeast Louisiana, where he was executed.
After court battles earlier this month, lawyers for Hoffman had turned to the Supreme Court in last-ditch hopes of halting the execution.
Last year, the court declined to intervene in the nation's first nitrogen hypoxia execution, in Alabama.
Hoffman's lawyers had unsuccessfully argued that the nitrogen gas procedure - which deprives a person of oxygen - violates the Eighth Amendment's prohibition on cruel and unusual punishment.
Louisiana officials maintained the method is painless.
They also said it was past time for the state to deliver justice as promised to victims' families after a decade and a half hiatus - one brought on partly by an inability to secure lethal injection drugs.
Under the Louisiana protocol, which is nearly identical to Alabama's, officials had earlier said Hoffman would be strapped to a gurney before a full-face respirator mask fitted tightly on him.
Pure nitrogen gas was then pumped into the mask, forcing him to breathe it in and depriving him of the oxygen needed to maintain bodily functions.
The protocol called for the gas to be administered for at least 15 minutes or five minutes after the inmate's heart rate reaches a flatline indication on the EKG, whichever is longer.
