The 20-year-old striker, who has signed a three-year deal, joined the Saints from Oxford United in 2003 and was a popular figure among fans.
Memorable moments included a hat-trick against Colchester and a goal against local rivals Portsmouth during the 2004/2005 season.
Blackstock moved down the pecking order after the arrival of Grzegorz Rasiak and Bradley Wright-Phillips.
"It's great to be here,'' Blackstock told www.qpr.co.uk
"It had all gone a bit stale for me at Southampton and the chance to move to London was just too good to turn down. It's a fresh challenge for me and I couldn't be any happier.
"I had a nice chat with Gary Waddock, who told me about the hunger and desire of the Rangers squad, so there was never any doubt I'd sign.
"I've always enjoyed playing at Loftus Road in the past, so I'm really excited about making my debut here.''