Nick Pope, Joe Willock, Anthony Elanga and Anthony Gordon all come in for the first leg match at the Tofiq Bahramov Republican Stadium in Baku, the Magpies' first ever knockout fixture in the star-studded competition.
Pope, an unused substitute in Saturday's Emirates FA Cup fourth round win against Aston Villa, returns in-between the sticks in place of Aaron Ramsdale.
Kieran Trippier, nearing 150 club appearances, captains the visitors in Azerbaijan while Malick Thiaw, Dan Burn and Lewis Hall all retain their spots in the defensive backline.
Willock, who scored in last month's 1-1 draw against Champions League holders Paris Saint-Germain, replaces Jacob Ramsey in the middle of the park and will feature alongside Sandro Tonali, who netted twice in United's FA Cup victory at Aston Villa last weekend.
Elanga and Harvey Barnes are likely to occupy the respective flanks while Nick Woltemade and Gordon will be the vocal points in attack this evening.
Gordon, who has six Champions League goals to his name so far this season, is one strike shy of equalling the club's all-time goalscoring record in the UEFA Champions League, held by Alan Shearer.
Joelinton has made a welcomed return to the matchday squad for the first time since suffering a groin injury in January's Premier League defeat against Aston Villa, with the Brazilian midfielder named as a substitute.
Jacob Murphy and Will Osula, who both started against the Villans in last weekend's FA Cup tie, are also on the bench along with young trio Alex Murphy, Sean Neave and Leo Shahar.
John Ruddy, who replaced Emil Krafth in United's UEFA Champions League squad as the Swedish defender withdrew due to injury, is named on the bench as well as teenage goalkeeper Aidan Harris.
Newcastle United: Nick Pope, Kieran Trippier (c), Lewis Hall, Sandro Tonali, Anthony Gordon, Harvey Barnes, Malick Thiaw, Anthony Elanga, Nick Woltemade, Joe Willock, Dan Burn.
Substitutes: John Ruddy, Aaron Ramsdale, Aidan Harris, Joelinton, Will Osula, Jacob Murphy, Alex Murphy, Jacob Ramsey, Leo Shahar, Sean Neave.
