The 25-year-old Netherlands international has joined the Premier League club for an undisclosed fee.
De Jong, who captained Ajax, made over 200 appearances for the club and scored 78 goals.
His younger brother, Luuk, spent six months on loan at Newcastle last season and the club's new signing is looking forward to the challenge of proving himself in England.
"It is great to have signed for Newcastle," De Jong told the club's official website.
"It is a big club which my brother told me all about, so I already feel good here.
"I had been at Ajax a long time and wanted a new challenge in a new environment and a new country.
"Coming to Newcastle is a great opportunity and the chance to play for a club like this in the Premier League was one I could not turn down.
"I am looking forward to starting training and meeting my new teammates and hopefully we can have a successful season."
Newcastle manager Alan Pardew said the signing was a statement of intent ahead of the new Premier League season.
"We are absolutely overjoyed to bring Siem to the club because he will give us intelligence in the final third and create goalscoring situations, which we lacked towards the end of last season," Pardew added.
"It is a big signing for this club. Siem brings massive experience from Ajax, I think our fans are going to enjoy the way he plays and I cannot wait to start working with him."
Newcastle finished a disappointing 10th in the Premier League last term.
