The Norwegian, second last year to Dario Cologna, edged out the Swiss by seven tenths and will gain an additional five bonus seconds.
Norway have not produced an overall champion in either the men's or women's event in the first five editions of the Tour de Ski with double Olympic champion Northug runner-up in each of the last three years.
The podium matched the top three in the World Cup standings with France's Maurice Manificat, four seconds back, taking third ahead of last year's prologue winner Marcus Hellner of Sweden.
Former champions Tobias Angerer and Lukas Bauer were 21st and 27th respectively with Britain's Andrew Musgrave just one place behind the Czech.
Justyna Kowalczyk began her bid for a third consecutive Tour de Ski title with victory in the women's 3.1km prologue.
The Pole posted a time of 7:03.7, four tenths quicker than current World Cup leader Marit Bjoergen.
The Norwegian has already posted four victories this season but could not match the defending World Cup champion in the free technique and will start Friday's 10km handicap 5.4 seconds behind Kowalczyk.
Hanna Brodin of Sweden was third, four seconds back, and will start 14 seconds behind the Pole after bonus seconds are awarded.
Finland's Riitta-Liisa Roponen and Marthe Kristoffersen completed the top five with last year's runner-up Therese Johaug in 14th, the distance specialist coming home 12.2 seconds off the leader's time.
The nine-stage, 11-day event finishes on January 8 in Val di Fiemme with the overall results based on the aggregate time for all the events, as well as bonus seconds awarded on sprint and mass start stages.
1 29 December - Oberhof (GER) - Prologue Free technique, individual start
2 30 December - Oberhof (GER) - Pursuit Classical technique, handicap start
3 31 December - Oberstdorf (GER) - Sprint Classical technique
4 1 January - Oberstdorf (GER) - Skiathlon Classical/Free technique, mass start
5 3 January - Toblach (ITA) - Distance Classical technique, individual start
6 4 January - Toblach (ITA) - Sprint Free technique
7 5 January - Cortina d'Ampezzo (ITA) - Distance Free technique, handicap start
8 7 January - Val di Fiemme (ITA) - Distance Classical technique, mass start
9 8 January - Val di Fiemme (ITA) - Final Climb Free technique, handicap start