Du Plooy is averaging 98.10 in the County Championship this season, with 981 runs and three centuries. He only took over as captain last year, after Billy Godleman stepped down, and despite his form Derbyshire are currently bottom of Division Two. In the Blast, they narrowly missed out on a quarter-final spot after defeat in their last group game.
Born in South Africa but eligible as a non-overseas player due to a Hungarian passport and pre-settled status in the UK, du Plooy has built a productive record across formats, winning contracts in the Hundred with Welsh Fire and Southern Brave, having also impressed in the SA20 for Joburg Super Kings.
"We are delighted that Leus has chosen to join Middlesex Cricket and are really excited about what he will bring to the group," Middlesex's director of cricket, Alan Coleman, said. "Leus is a player that we have admired for a long time, and he will make a significant difference to our squad in all forms of the game.
"The fact that Middlesex were one of several counties chasing his signature, with his contract with Derbyshire finishing this year, is testament to not only his abilities as a cricketer but to him as an individual, and we are just so pleased that he'll be heading to Lord's. He is the kind of player and person who will add so much to our dressing room.
"The fact that he is Southern Brave's most expensive domestic signing this year in the Hundred, in the top value bracket of players, shows what a world-class striker of the ball he is, and he will be a huge boost to our T20 squad as well as our red-ball squad.
"We can't wait to welcome Leus to Lord's and look forward to him enjoying a long and successful career with the club. He will play a big part of everything we are looking to achieve moving forwards here at Middlesex."
In first-class cricket, du Plooy averages 47.17, with 18 hundreds. He has also scored more than 2500 career runs in T20, at a strike rate of 133.50.
"I'm incredibly honoured and extremely excited to begin this new chapter with Middlesex Cricket," du Plooy said. "Lord's is a special place to play, and it'll be surreal to call it my home ground next year.
"I'm really looking forward to meeting everyone and forming new relationships, creating special memories and improve my game at such a prestigious club."