The three drug method first sedates the inmate, then paralyses the muscles and finally stops the heart.
If the execution goes to plan, the prisoner quickly loses consciousness and dies in a few minutes but if the anaesthesia is not properly administered, the inmate can suffer immensely.
In a December 2006 Florida execution, Angel Nieves Diaz, a convicted murderer, had to be given two lethal doses after a needle missed his vein. His execution took 34 minutes to complete.
States began using the three-drug lethal injection method in 1978 as an alternative to electrocution, the gas chamber, hanging and shooting.
John Roberts, the court's chief justice, said the petitioners had not shown that "the risk of pain from maladministration of a concededly humane lethal injection protocol, and the failure to adopt untried and untested alternatives, constitute cruel and unusual punishment."
"The alternative procedure must be feasible, readily implemented and in fact significantly reduce a substantial risk of severe pain," he said.
The ruling was released on the same day the justices heard arguments in another major death penalty case.
The court considered the constitutionality of the death penalty for child rape, the first test in more than 30 years of whether a crime other than murder can be punished by execution.
Executions in the US fell to a 13-year low of 42 in 2007, and had been halted since the court agreed in September to decide on the challenge.
Around two-thirds of Americans support the death penalty, according to the Death Penalty Information Center, in a country where 3,260 detainees are presently on death row.