The 27-year-old German, whose ranking of 162 is the highest of his career, beat 27th-ranked Seppi 6-2, 5-7, 6-4 in their first-round match on the red clay of Gstaad.
Meffert had to win two qualifying matches to reach the main draw of the $625,000 event.
Seppi was the runner-up in Gstaad last year and reached the semifinals of the Masters Series event on clay in Hamburg, Germany, in May, losing to Roger Federer in two sets.
Sixth-seeded Nicolas Kiefer of Germany eased past Italy's Gianluca Naso 6-3, 6-2.
Top-seeded Stanislas Wawrinka has a bye to the second round, where he will face Stephane Bohli. Defending champion and second-seeded Paul-Henri Mathieu will play Marin Cilic of Croatia in the second round.