Southee follows fellow Kiwi Brendon McCullum in joining the club, who are coached by former New Zealand spinner Daniel Vettori in Twenty20 cricket.
The 28-year-old has taken 46 wickets at an average of 26.71 in 39 Twenty20 international games.
His only previous English domestic T20 spell came with Essex in 2011, when he took 22 wickets in 15 games.
"I'm excited to be joining Middlesex this year for the NatWest T20 Blast and helping the club throughout the T20 competition," he said.
"When the opportunity come up to play for Middlesex it wasn't a tough decision to make."
Middlesex have signed New Zealand seamer Tim Southee as their second overseas signing for the T20 Blast.