A youthful Under-21 team, including eight starters aged 18 or younger, took a 2-0 lead in the opening 16 minutes against their League One opponents, with Callum Hudson-Odoi pivotal in both goals as Harvey St Clair and Daishawn Redan found the net.
Juan Castillo settled the match at Stamford Bridge with 25 minutes left, curling a superb strike past Oxford goalkeeper Simon Eastwood.
Sixteen Under-21 sides have been competing against 48 senior League One and League Two sides in the competition since the 2016/17 season, giving Academy youngsters experience of senior football alongside the Professional Development Phase programme at Under-23 level.
See: Chelsea report
Lincoln City v Chelsea U21, 7:45pm, Tuesday 6 February
Shrewsbury Town v Yeovil Town/Fleetwood Town, 7:45pm, Tuesday 27 February