Nieves, 55, who was convicted of killing a bar manager in 1979 but maintained his innocence, appeared to grimace before dying in the 34-minute execution.
A spokesperson for the state's Department of Corrections, Gretl Plessinger, said she did not believe Nieves had felt any pain. He had liver disease, which required the second dose, she said.
"It was not unanticipated. The metabolism of the drugs to the liver is slowed," she said.
In a short, written statement, the office of Florida Governor Jeb Bush said late Wednesday that "the Department of Corrections followed all protocols in place ... a preexisting medical condition of the inmate was the reason tonight's procedure took longer than recent procedures carried out this year."
For Mark Elliot, a spokesperson for Floridians For Alternatives to the Death Penalty, the Nieves execution was inhumane.
If Nieves was conscious during the administration of the third chemical of the lethal cocktail, potassium chloride, the pain would have been excruciating since the chemical burns the internal organs, Elliot said.
"The first two chemicals administered are an anesthetic and a paralyzing agent," he said. "If they don't take effect by numbing and rendering the prisoner unconscious, then the death is agonizing."
One of Nieves's grounds for appeal of his death sentence had been that Florida executions constitute cruel and unusual punishment, which is prohibited by the Eighth Amendment of the US Constitution.
Maria Otero, a cousin of Nieves, moved to Orlando, Florida, 21 years ago to be close to him.
"We want justice, this isn't over," she said. This (fight) will go on, this is what Angel wanted," said Otero in an interview with AFP.
Otero was not a witness to the execution, but was outside the death chamber in Starke, Florida. She spoke of the reports she got from witnesses.
"Angel suffered a lot, a first injection, then another, and after that first injection his eyes -- he was looking up and down, had spasms in his chest and Angel wouldn't die. Angel's case has taken the lid off this can of worms", she said.
Otero said that she and her family would meet with an attorney to explore filing a suit against the state.
Witnesses also said that when Nieves was strapped on the gurney, he said, "The death penalty is not only a form of vengeance, but also a cowardly act by humans."
Nieves, born in the Spanish-speaking US territory of Puerto Rico, was the 53rd person executed in the United States this year and probably will be the last because no other execution is scheduled before January. In 2005, the US executed 60 convicts.
On December 29, 1979, two men held up the Velvet Swing Lounge, a topless bar, and manager Joseph Nagy was fatally shot. They were quickly arrested but their cases only went to trial in December 1985.
Angel Toro pleaded guilty in exchange for life imprisonment. Nieves repeatedly denied that he had shot Nagy and refused to enter a plea bargain with prosecutors.
The governor of Puerto Rico, Anibal Acevedo Vila, and the conference of Roman Catholic bishops in Florida had written to the Florida governor appealing Nieves's death sentence.
"The people of Puerto Rico have a longstanding, unwavering and broadly accepted commitment against the death penalty for moral, social and religious reasons," Acevedo wrote.
What a load of shit. "Justice"? How about Joseph Nagy? Why did it take 27 years before his family got justice? Why are people so fucking concerned over Nieves but barely a single word has been said about the victim in this case?
By the way: In case you have not heard, there is now a moratorium on executions in Florida until a commission finds out, "what went wrong."