Despite netting the winning goal in Juve's 2-1 defeat of Fiorentina last time out, the Argentina star was still was not fit enough to start, but that ultimately mattered little, as Khedira scored just a few moments after the striker's 65th-minute introduction.
There was nothing to separate the two sides during a tepid first half in Rome, with the respective defences on top and clear-cut chances rare.
But the second period started with an instant improvement as Juve took the game to their hosts, with Mario Mandzukic, Paulo Dybala and Khedira all going close in a frenetic four-minute spell.
The German was not to be denied twice, though, as he fired across Federico Marchetti 24 minutes from time to put victory in the visitors' sights,
Juve then proceeded to tighten their hold on the match and, while Lazio pressed for a late equaliser, the champions had little trouble keeping them at bay to make it two wins from two.
After only stealing victory late on against Fiorentina last time out, Juve looked intent on putting Lazio under pressure significantly earlier at Stadio Olimpico and went close to breaking the deadlock 10 minutes in.
Alex Sandro charged down Dusan Basta's clearance and the ball dropped kindly for Dybala, whose header forced Marchetti to scramble across his goalline and desperately push it away.
The hosts grew into the match, though, and caused some panic of their own in the Juve defence, as Felipe Anderson's right-wing delivery flashed across the goal and forced Dani Alves into an acrobatic clearance before Ciro Immobile could nod in with 24 minutes gone.
That proved to be an isolated moment of worry for Juve, whereas Marchetti was again forced to clamber 10 minutes later, just about stopping Kwadwo Asamoah's deflected volley from creeping under the crossbar.
Proceedings became more frantic after the break and Juve went close twice in quick succession early on – Mandzukic blasting at Marchetti from 18 yards, before Dybala fired just wide of the right-hand post from the rebound.
Higuain was eventually brought on in the 65th minute and Juve had the lead a minute later.
The goal came from a more unlikely source, though, as Khedira latched on to Dybala's pass into the right side of the area and the German found the bottom-far corner with a smart finish.
Lazio's efforts failed to produce any clear opportunities and, when Marco Parolo's long-range effort was comfortably gobbled up by Gianluigi Buffon five minutes from the end, the hosts' chances of a late comeback were effectively ended.