The 26-year-old world No.68 showed too much fight for the inconsistent defending champion Barthel, whose occasional smoking winners were undone by a service game that let her down badly.
The loss ended a 12-match winning streak in Hobart after world no.32 Barthel had to qualify before winning the title last year.
Vesnina, who was ranked as high as No.22 in 2009, becomes the second Russian to win the event after Anna Chakvetadze in 2007 and takes home $US40,000 ($A37,900) in prize money.
She ousted seeds Yaroslava Shvedova and Sloane Stephens, as well as Australian wildcard and former champ Jarmila Gajdosova, on her way to the final.
Some superb shot-making from Barthel in the first was cruelled by the 22-year-old's inability to land more than 27 per cent of her first serves.
She was broken in the first game of the match and, although, she broke back for 2-2, her inconsistency allowed the tenacious Vesnina to break twice more.
The Russian converted her first set point when Barthel hit wide to take the set in 35 minutes.
Barthel looked to be mounting a comeback when she broke early in the second set for 2-1 but the German surrendered her next service game and Vesnina smelled blood.
She took a 3-2 lead when she held with a superb drop shot and had Barthel down 0-40 before the defending champ fought back and held for 3-3.
Vesnina saved two break points in the seventh game before holding with her first ace.
Looking by far the more solid of the two, she converted her first match point when Barthel hit a backhand wide to win in an hour and 24 minutes.
Vesnina will now take plenty of confidence into her first round match against French world No.164 Caroline Garcia at the Australian Open.
Barthel will play Kazakhstan's world No.79 Ksenia Pervak.