Real Madrid must go through the UEFA Champions League play-offs and a tie against either Manchester City or Celtic after failing to finish in the top eight despite comfortably beating Brest 3-0.
A Rodrygo double and Jude Bellingham's strike secured a win for the reigning champions, who needed a win in France to stand a chance of an automatic place in the round of 16.
But results elsewhere mean Carlo Ancelotti's side must play an extra two-legged tie if they are to defend their title.
Brest also go into the knock-out play-offs in their debut Champions League campaign.
After a slow start, Madrid assumed control in Guingamp and deservedly took the lead after 27 minutes through a fine goal from Rodrygo.
The Brazilian, who now has 10 goals in as many matches, cut inside a defender on his right foot, before shimmying back onto his left and striking a low effort in off the far post.
Madrid suffered a mighty scare as Ludovic Ajorque squeezed home a shot deflected off Aurelin Tchouameni, only to be determined narrowly offside following a Video Assistant Referee (VAR) review.
Instead, Bellingham made it 2-0 after 57 minutes when he finished from Lucas Vazquez's cutback, and Rodrygo added a third by turning in the rebound from a Marco Bizot save.
Victories for Bayer Leverkusen, Lille and Aston Villa meant it was mathematically impossible for Madrid to reach the top eight no matter their result.
Instead the European champions finish 11th, and will face one of Manchester City or Celtic in the play-offs with the draw to be made on Friday (Jan 31).
Brest come 18th, and will face Benfica or Ligue 1 rivals Paris Saint-Germain in the next round.
