The British number two defeated world number 27 Varvara Lepchenko 6-3 6-4 to set up a second-round clash with Russia's Elena Vesnina.
Watson spent two months out with the illness before returning at the French Open and posted her first win in Birmingham last week against Melinda Czink.
American Lepchenko was certainly a step up and represents one of the best wins, rankings-wise, that Watson has had in her career.
Things did not begin well for the 21-year-old, who dropped her serve in the opening game, but she hit straight back and then broke again to lead 4-2 before serving out the first set.
The second set was extremely tight and Watson was under pressure for much of it but she hung on and then broke in the ninth game, saving one break point as she clinched victory on her first match point.
"After losing last week in Birmingham I felt really up for this match and wanted to do well here in Eastbourne," said Watson.
"I put in a couple of good days' practice here on the grass and I'm feeling very motivated to do well here."
Vesnina, meanwhile, pulled off a first-round upset with a 2-6 6-4 6-3 win over seventh seed Ana Ivanovic.
Sixth seed Maria Kirilenko did progress though, Also through to round two are former Wimbledon finalist Marion Bartoli and Belgium's Yanina Wickmayer, while a notable result in qualifying saw Kristyna Pliskova beat twin sister Karolina.