David Moyes takes his side to eastern Europe hoping to bounce back from defeat at home to West Brom in the Red Devils' first ever meeting with Mircea Lucescu's impressive outfit.
The two sides come into the game having won their opening Group A fixtures, with Shakhtar defeating Real Sociedad 2-0 in Spain, while United ran out a 4-2 victor over Bayer Leverkusen at Old Trafford.
Shakhtar has won all three of its previous home fixtures against English opposition in the Champions League, with successes over Arsenal in 2000-01 and 2010-11, before last season’s 2-1 victory over Chelsea, which helped eliminate the English side.
United’s last visit to Ukraine was a successful one, though, ending in a 4-2 win over Dynamo Kiev in the 2007-08 group stage.
Mircea Lucescu's men head into the fixture on the back of a run of inconsistent league form, having won only one of the past five matches in the Ukrainian Premier League - a division the club has won for the last four consecutive seasons.
The team currently sits third in the table, having dropped 10 points from the opening 11 games - just one less than it missed out on in the whole of the last campaign.
Shakhtar's latest outing saw the team come from two goals down to rescue a point against local rival Metalurh Donetsk, with Eduardo coming off the bench to bag the equalizer with eight minutes remaining.
United, under new manager David Moyes, has also struggled for form domestically this season.
The three-time European champion has taken just seven points from its first six Premier League games - the team's worst start to a season since the 1989-90 campaign.
Moyes came in for criticism following Saturday's 2-1 home defeat at the hands of West Brom, a result which leaves the reigning English champion eight points adrift of early leader Arsenal.
However, the former Everton boss will have Nani available for the trip to Donetsk after the Portuguese winger missed the opening game through suspension following his red card in last season’s exit to Real Madrid.
Wayne Rooney’s two goals against Leverkusen made him the all-time leading British scorer in the competition with 29 goals, while Robin van Persie’s strike in the same game means he has now scored in 10 consecutive Champions League seasons.