With a chill wind blowing and drizzle falling on the Simonne-Mathieu arena, the 40-year-old Williams began strongly but got bogged down in a baseline battle on a slow surface.
The American has now fallen in the opening round at the French Open for the past three years.
Williams led 3-1 and 4-2 in the first set against the 26-year-old who is playing under a special ranking after undergoing knee surgery.
But she lost a series of lengthy games as a first set lasting 68 minutes slipped away.
Unable to hold her once mighty serve, Williams, the oldest player in the draw, fell 4-1 down in the second set.
This came as Schmiedlova moved within sight of snapping a streak of 12 successive Grand Slam first round defeats since 2016.
Williams, who played in black leggings and a bodywarmer, finally held serve.
That was after being broken six times in a row to close to 3-4 in the second as Schmiedlova began to look a little nervy.
But the Slovak edged 5-3 in front.
Seven-times Grand Slam champion Williams fought ferociously until the end, saving two match points on serve.
But Schmiedlova showed great composure to serve it out, sealing victory with a forehand down the line.
Williams, playing her 87th Grand Slam and now ranked 76th in the world, also lost in the opening round at the U.S Open.
It was the first time she had fallen at the first hurdle at her home Slam in 22 appearances.(Reuters/NAN)
•PHOTO: Venus Williams

NPFL: Rangers win big as Nasarawa shock Abia
Nigeria know World Table Tennis Champs foes today
Bayelsa athletics boss Oredipe maps out dev plans
Falcons stars dominate IFFHS Africa XI
Eguavoen backs NPFL talents for Nigeria squad despite CHAN failure
He’s very strong, Simeone returns Osimhen praise
Joshua boxing return still uncertain
NBA star Bane eyes Nigeria switch
Palmer 'very, very happy' at Chelsea, says Rosenior
AFCON 2025: VAR recording discloses what referee said before Morocco's penalty miss against Senegal
AFCON 2025 highlights: World-class stadiums, VAR drama, record attendance
Oliseh slams Osimhen for costing Eagles’ AFCON trophy
Rangers International going, going . . . (63,494 views)
Amaju Pinnick: A cat with nine lives (54,787 views)
Second Term: Amaju Pinnick, Other NFF Heavyweights Home to Roost •How Pinnick Broke the Jinx (52,684 views)
Current issues in Nigerian sports: Matters arising (52,344 views)
Sports Development: Zenith Bank on the zenith (52,276 views)
Missing $150,000 IAAF Grant: Solomon Dalung’s Hide and Seek game (52,187 views)
Gov. Abdullahi Ganduje’s solid footprints, commitment to sports development in Kano State (52,054 views)
NFF Presidency: Pinnick, Maigari, Ogunjobi, Okoye in Battle for Supremacy (51,608 views)
Olopade, BET9A wave of revolution in NNL (50,787 views)
Commonwealth Games 2018: Shame of Muhammadu Buhari, Solomon Dalung (49,314 views)
Ibrahimovic’s Man U exit: Whose decision is it? And in whose interest? (47,704 views)
John Mikel Obi: Segun Odegbami’s Outrageous Call! (47,172 views)