Ferrer, who has slipped to 39th in the rankings, went down to 21-year-old Russian Karen Khachanov 6-7 (5-7) 6-3 6-4 in Montpellier.
The Spanish seventh seed, a semi-finalist in Auckland to begin the year, was beaten after two hours and 28 minutes.
Julien Benneteau, a finalist in 2008, went out 6-3 7-6 (8-6) to Ricardas Berankis but Simon beat qualifier Yannick Maden 6-1 4-6 7-6 (7-3) and Jeremy Chardy overcame promising Greek teenager Stefanos Tsitsipas 4-6 7-5 7-5.
Carlos Taberner was also a victor over Norbert Gombos in a battle of two qualifiers.
At the Sofia Open, sixth seed Viktor Troicki came through a stern test from qualifier Ernests Gulbis to win 6-3 6-7 (2-7) 6-3.
Martin Klizan beat Alexander Donski 7-5 6-1 to set up a second-round clash with Stan Wawrinka and there were also wins for Denis Istomin, Mirza Basic and Jozef Kovalik.