After Lee managed to pull one back for humanity in game four, AlphaGo returned to its best destructive form, using the much-hyped "intuitive" artificial intelligence (AI) of its formidable neural networks to outwit the 33-year-old Lee.
A visibly upset Lee held his head in his hands at the table after resigning at the end of a five-hour battle.
It was a disappointing finale for the South Korean who has 18 international titles under his belt and is widely considered one of the greatest Go players of the modern era.
The "machine vs human" element meant the games also made headline around the world, with AlphaGo's winning performance hailed as a watershed for the future of AI.
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The most famous AI victory to date came in 1997, when the IBM-developed supercomputer Deep Blue beat the then-world class chess champion Garry Kasparov.
But Go, played for centuries mostly in Korea, Japan and China, had long remained the holy grail for AI developers due to its complexity and near-infinite number of potential configurations.
It also employs algorithms that allow it to learn and improve from matchplay experience.
Its creators, DeepMind, say the technology has far-ranging, real-world applications from making smartphones smarter to health care.
Before the final game, South Korea's Go Association said it was awarding AlphaGo the highest Go grandmaster rank of "ninth dan", reserved for those whose ability at the ancient board game borders on "divinity.