In March 2016, he played a notable series of matches against the program AlphaGo that ended in Lee losing 1–4.

[2] On 19 November 2019, Lee announced his retirement from professional play, stating that he could never be the top overall player of Go due to the increasing dominance of AI.

[3] In a 2024 New York Times article, Lee said, "losing to AI, in a sense, meant my entire world was collapsing."

Lee, playing black, defied the conventional wisdom, using the broken ladder to capture a large group of Hong's stones in the lower-right side of the board.

[12][13][14] He said “I have heard that Google DeepMind’s AI is surprisingly strong and getting stronger, but I am confident that I can win at least this time”.

[15] In an interview with Sohn Suk-hee of JTBC Newsroom on 22 February 2016,[16] he showed confidence in his chances again, while saying that even beating AlphaGo by 4–1 may allow the Google DeepMind team to claim its de facto victory and the defeat of him, or even humanity.

In another interview at Yonhap News, Lee Se-dol said that he was confident of beating AlphaGo by a score of 5–0, at least 4–1 and accepted the challenge in only five minutes.

[23] After his fourth-match victory, Lee was overjoyed: "I don't think I've ever felt so good after winning just one match.

"[25] On 19 November 2019, Lee Sedol announced his retirement from professional play, stating that "Even if I become the number one, there is an entity that cannot be defeated.

"[3] However, in December he agreed to play a three-game match against the HanDol AI system, developed by Korean NHN Entertainment Corporation.

[26] HanDol subsequently won the remaining two games of the match, with a final score of two-to-one, winning the overall contest.