See main article: 2009 Copa Libertadores. The last four stages of the 2009 Copa Santander Libertadores are the knockout stages: the Round of 16, the Quarterfinals, the Semifinals, and the Finals.
The remaining stages of the tournament constitute a single-elimination tournament. In each stage, the teams will play an opponent in a two-legged tie on a home-away basis. Each team will earn three points for a win, one point for a draw, and zero points for a loss. The team with the most points at the end of each tie will advance.
The following criteria will be used for breaking ties on points:
The 16 qualified teams in the knockout round will be seeded according to their results in the group stage. The top teams from each group are seeded 1-8, with the team with the most points as seed 1 and the team with the least as seed 8. The second-best teams from each group are seeded 9-16, with the team with the most points as seed 9 and the team with the least as seed 16. Teams with a higher seed will play the second leg of each tie at home.
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The Round of 16 began on May 5. Team #1, as the higher seeded team, played the second leg at home.
| Teams | Scores | Tie-breakers | ||||||
|---|---|---|---|---|---|---|---|---|
| Team #1 | Team #2 | 1st leg | 2nd leg | |||||
Grêmio  | 6:0 |  Universidad San Martín | 3–1 | 2–0 | — | — | — | |
Boca Juniors  | 1:4 | Defensor Sporting | 2–2 | 0–1 | — | — | — | |
| Nacional | w/o |  San Luis | — | — | — | — | — | |
| São Paulo | w/o | Guadalajara | — | — | — | — | — | |
| Cruzeiro | 6:0 | Universidad de Chile | 2–1 | 1–0 | — | — | — | |
| Sport Recife | 3:3 | Palmeiras | 0–1 | 1–0 | 0:0 | 0:0 | 1:3 | |
| 1:4 | Estudiantes | 0–3 | 0–0 | — | — | — | ||
Caracas  | 3:3 |  Deportivo Cuenca | 1–2 | 4–0 | +3:−3 | — | — | |
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Sport Recife 3–3 Palmeiras on points, Sport Recife & Palmeiras tied on goal difference and goals scored. Palmeiras won 3–1 on penalties.----Caracas 3–3 Deportivo Cuenca on points. Caracas won +3 on goal difference.----Grêmio won 6–0 on points.----Cruzeiro won 6–0 on points.----Estudiantes won 4–1 on points.----Defensor Sporting won 4–1 on points.
Team #1, as the higher seed, will play the second leg at home.
| Teams | Scores | Tie-breakers | ||||||
|---|---|---|---|---|---|---|---|---|
| Team #1 | Team #2 | 1st leg | 2nd leg | |||||
| Grêmio | 2:2 | Caracas | 1–1 | 0–0 | 0:0 | 1:0 | — | |
| Estudiantes | 6:0 | Defensor Sporting | 1–0 | 1–0 | — | — | — | |
| Nacional | 2:2 | Palmeiras | 1–1 | 0–0 | 0:0 | 1:0 | — | |
| São Paulo | 0:6 | Cruzeiro | 1–2 | 0–2 | — | — | — | |
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Nacional 2–2 Palmeiras on points. Nacional and Palmeiras tied on goal difference and goals scored. Nacional advances on away goals.----Grêmio 2−2 Caracas on points. Grêmio and Caracas tied on goal difference and goals scored. Grêmio advances on away goals.----Estudiantes advances 6–0 on points.----Cruzeiro advances 6–0 on points.
| Teams | Scores | Tie-breakers | ||||||
|---|---|---|---|---|---|---|---|---|
| Team #1 | Team #2 | 1st leg | 2nd leg | |||||
| Grêmio | 1:4 | Cruzeiro | 1–3 | 2–2 | — | — | — | |
| 0:6 | Estudiantes | 0–1 | 1–2 | — | — | — | ||
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Estudiantes advances 6–0 on points.----Cruzeiro advances 4–1 on points.
See main article: 2009 Copa Libertadores Finals. The Finals was played on July 8 and 15.|}
A. Guadalajara and San Luis withdrew from the tournament following concerns raised by both Nacional and São Paulo over the H1N1 flu outbreak in Mexico, South American teams refused to travel to Mexico to play the match; no agreement was reached on alternative venues for the first-leg matches, both scheduled to be played in Mexico. Both Guadalajara and San Luis were later secured a place in the round of 16 for the 2010 Copa Libertadores.l.