The 22-year-old has scored 54 goals in the past two seasons for the Pilgrims.
Southwell, formerly of Grimsby Town, was named in the National League North team of the year and also earned his first international cap for the England C over the summer, adding another accolade to his growing list of achievements.
Wycombe boss Gareth Ainsworth said: “Dayle is a player who’s been on our radar for some time and I’m thrilled to be able to bring him here. There were a lot of clubs looking at him but we know we can offer him a real opportunity to make his name in the Football League and develop his potential even further.
“He’s a physical striker who knows where the goal is and I’m confident that his all-round play will benefit us. It’s a great step up for Dayle and I think he could prove to be a really exciting signing for us”.