Unlike Laura Robson and Elena Baltacha, Watson won a set and pushed her opponent all the way, but it was ultimately in vain as Swiss Voegele won 6-4 2-6 6-4 on Court Six at Roland Garros.
Watson's defeat in a match delayed for a day by rain means there is no British player in the second round of the singles in Paris for the first time since 2007.
It was always going to be a tough ask for the British number two after more than two months out with glandular fever, but the good news is Watson is not too far away.
Her movement and consistency were not quite up to their usual standards but she will have high hopes of performing well on grass.
Watson may have been suffering from glandular fever since December but she battled on for the first three months of the year before a blood test in Miami showed what the problem was.
She returned to light training three weeks ago and has been working back up to her usual volume, rating herself at 90-95 per cent prior to the start of the tournament.
Voegele, ranked eight places below world number 48 Watson, was the steadier player in the opening set, with one break of serve in the fifth game enough for the Swiss player to take it.
Watson saved two set points on her own serve trailing 5-3 but could not put enough pressure on the serve of her opponent, who was beaten by Baltacha in Brussels last week.
The 21-year-old from Guernsey stepped things up at the start of the second set, her forehand beginning to cause some damage, and, after saving four break points in the opening game, gained her first break.
Back came Voegele but she was not having an easy time on her serve now and Watson broke again in the sixth game, earning plenty of cheers from the sizeable British contingent in the crowd, and she clinched the set with another break.
But she could not carry the momentum into the decider and a break in the first game ultimately proved decisive, although Watson thought she had made a forehand and protested at length to umpire Pascal Maria.
The British player's best chance of retrieving the break came in the eighth game but three opportunities came and went, and her hopes of a comeback were ended soon after.
The disappointment for Watson is this is a venue where she has done well in the past, qualifying and reaching the second round on both her previous appearances, but she should not fall too far in the rankings.