Since being drafted in 2003, he has won two Super Bowls with the Pittsburgh Steelers and was awarded the 2010 defensive player of the year.
Last year he missed four of the last seven games of the season because of a knee injury.
He says that ending his professional career will give him a chance to "enjoy" his family.
The Pittsburgh Steelers, the only team he has ever played professionally for, had asked him to retire earlier this year but he said he only agreed to the idea this week.
"What it came down to was definitely family," he told Scout.com, revealing that he did not want to play elsewhere in the US.
"What am I going to do now? I think the best I can do is make up for lost time, and that's with my family."
Polamalu has two sons, aged seven and five, with his wife Theodora.
"Thank God football has provided me the ability to be able to sit back and see what the options are. But I'll definitely be the best father I can possibly be."
Born in the US, Polamalu is of Samoan descent. He is known for his iconic hairstyle, which he used to advertise shampoo.
Speaking in 2010, he revealed that he had not cut his mass of hair for about a decade.
Polamalu is part of the Greek Orthodox faith and he said that some of the numbers surrounding his retirement also appealed to him.
"Thirty-three is obviously significant because of Christ being 33; and 12 years, 12 apostles," he said.
"I'm not superstitious by any means but I always thought that if I played 12 years and retire from football at 33 and give my life and give my body and give my blood to this game, I think that would be a pretty significant landmark in my life."
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Troy Polamalu, one of the best safeties in history, is retiring from the NFL after 12 seasons.