The Ukrainian powerhouses travelled to Germany holding the underdogs tag, but a goal and two assists from 21-year-old Mudryk helped the visitors pull off a shock result against Domenico Tedesco's side.
Mudryk started on the left-hand side of the attack for Igor Jovicevic's team, who had the ball in the net with just 16 minutes on the clock following a howler from Peter Gulacsi.
The Leipzig number one was midway inside his own half when receiving a back pass, but he dithered and comically laid the ball on a plate for Maryan Shved to score into an open net from a good 30 yards.
Shakhtar's resilience would soon be broken in the 57th minute when defender Mohamed Simakan crashed home the equaliser at the back post, but Mudryk would soon steal the show to propel his side to a mammoth success.
Leipzig fans barely had time to resettle after Simakan's equaliser before Shakhtar took the lead again, as Mudryk produced some neat step-overs before laying the ball off for Shved to bag his second of the contest, albeit with the help of a wicked deflection off the leg of Willi Orban.
With Jovicevic's team managing to absorb the Leipzig pressure well, Shakhtar broke forwards on the counter-attack in the 76th minute, as Mudryk raced through the middle to meet Georgiy Sudakov's pass and fire home into the bottom corner.
The visitors' dream night did not end with the 21-year-old's strike, as Mudryk got past Simakan and beat the offside trap before setting up substitute Lassina Traore for a tap-in.
The 21-year-old's tally took him up to three goals and 12 assists in 30 senior appearances for Shakhtar, as well as marking his first-ever goal in European competition.
Arsenal are understood to have been alerted to Mudryk's qualities after the youngster scored two goals and set up seven more in 11 Premier Liga outings last term, while Brentford were also rumoured to be keeping an eye on him.
However, the five-cap Ukraine international only signed a contract extension with Shakhtar until the summer of 2026 back in February, and bids of up to £30m were supposedly turned down last month.
Journalist Fabrizio Romano claims that Shakhtar value Mudryk at over €50m (£43m), and his stock is set to rise even further following his man-of-the-match showing at the Red Bull Arena.
Meanwhile, Leipzig boss Tedesco could now face the axe, according to Romano, with Die Roten Bullen lining up Marco Rose as his potential successor.