The Russian sixth seed had been beaten in her previous five finals, but got over the line with an impressive display at the final grass-court warm-up tournament before Wimbledon.
"It's been a year but it feels like only a few days since the final last time," the 27-year-old, who lost in last year's Eastbourne final to Madison Keys, said.
"It was a tough battle today. It's been a long road to the title but I am really proud."
Kasatkina broke Fernandez early and survived a marathon 20-minute game on her own serve midway through the opening set before going on to win it.
She moved 3-0 ahead in the second set before Fernandez, US Open runner-up in 2021, reeled off four successive games to put herself right back in it.
Kasatkina stopped the rot, though, and polished off the last three games to collect her first title since 2022.
The Russian is seeded 14th at Wimbledon and will face China's Zhang Shuai in the first round.
In the equivalent men's event on Britain's south coast, American Taylor Fritz beat Australia's surprise finalist Max Purcell 6-3 6-4 to claim his third Eastbourne title.
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