The Barcelona star stole the show with three goals to help the two-time World Cup winners earn the spoils against Ottmar Hitzfeld's men
The match looked headed for a draw after Xherdan Shaqiri cancelled out the Argentine's first-half effort with a goal early in the second period but the Barcelona star scored twice late on to secure victory.
Looking to build off a win against Colombia in World Cup qualifying in November, the South Americans showed pace and creativity in the early minutes, but did not pose much of a threat, as Ottmar Hitzfeld's defence was up to the task.
Fans were forced to wait nearly 20 minutes to see the match's first real chance. Messi found Sergio Aguero at the top of the box and the Manchester City striker rolled the ball back to his attacking partner. Messi composed himself, and fired a brilliant low shot from 20 yards into the right corner for the early advantage.
In the following minutes, Alejandro Sabella's men controlled the majority of the possession as they looked for their second goal, but the crucial pass to send a player through was missing from their play.
Switzerland responded, and the first half ended with the home team infiltrating the visiting area on numerous occasions, nearly equalising through Granit Xhaka, who drilled an effort over Sergio Romero and the crossbar from 16 yards.
In the second half, the maintained the momentum, and were deservedly level. In the 49th minute, Shaqiri curled the ball into the top corner with one touch after Stephan Lichtsteiner's cross somehow found its way to the soon-to-be Bayern Munich star.
With things level, both nations searched for the winning goal. Aguero nearly delivered with a poked shot from the middle of the box, but Marco Wolfli reacted quickly to slap the ball over the crossbar.
Messi left things late, clinching the win with a solo effort, running to the left side of the box before lifting the ball over the charging goalkeeper before it hit the crossbar and bounced down into the goal.
He added another in injury time after Gonzalo Higuain was brought down in the box, sending the Swiss custodian the other way from the spot to cement the result.
The home team next return to action at the end of May when they host Germany in a friendly, while the South Americans will face Ecuador in early June in a World Cup qualifying match.