The 20-year-old came from a set down to edge victory in the second, before staging a confident comeback in the third to reach the semi-finals of the Shanghai Open, as well as qualify for the ATP Tour finals.
Despite a shakey start, which saw Djokovic break Tsitsipas's opening serve, but the playing the World No.1 forced the Greek to step up in the second set.
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After narrowly beating Djokovic in the second, Tsitsipas's confidence grew in the third, breaking the Serb's second serve and preventing him from getting a foot back in the decisive set.
As well as taking his historic place in the Tour Finals next month, Tsiitsipas also becomes the first man to defeat Djokovic in Shagnhai before the semi-finals stage of the tournament.
Tsitsipas will face Daniil Medvedev in the semi-final, after he beat Fabio Fognini in the quarter-finals.
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