Graeme Armstrong's first-half strike was enough to earn Gateshead the advantage in the Blue Square North semi-final first leg at Haig Avenue.
The Gateshead striker hit a 15th-minute close-range winner after a long ball into the box had caused confusion in the home defence.
The Sandgrounders had their chances but could not find a way through,
And that makes Ian Bogie's Gateshead favourites for Sunday's second leg at the International Stadium (1700 BST)
Southport: McMillan; Lever, Gray, Flynn, Davis, Moogan, Booth, Winn, Daly, Whalley, McGinn. Subs: Prince, Atkins, Moore, Powell, Mitchley
Gateshead: Musselwhite; Baxter, Cave, Gate, Curtis, Jones, Harwood, Turnbull, Armstrong, Novak, Phillips. Subs: Stamp. Provett, Dinning, Hocking, Tunbull
Scorer: Armstrong (15)
Referee: Paul Graham (Manchester)
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