Andrea Pirlo gave the Bianconeri the lead with an early free-kick, but the league leaders were pegged back in first-half stoppage time by Emanuele Calaio's equaliser.
However, the visitors refused to settle for the draw and secured all three points five minutes from time when Marchisio volleyed home the winner.
Juve, under the interim guidance of technical director Massimo Carrera while coach Antonio Conte serves his suspension for failing to report match-fixing, headed into the game on a 45-match unbeaten run and did not take long to settle.
They took the lead in the 14th minute when Italy playmaker Pirlo stepped up to despatch a low free-kick into the bottom-right corner. Siena goalkeeper Gianluca Pegolo got a hand to the ball but could not keep it out.
Sebastian Giovinco passed up a fine chance to extend Juventus' advantage seven minutes later when he lashed over from close range.
It was not all one-way traffic, though, as Calaio's left-footed shot midway through the first half skimmed the left post.
The woodwork again played its part six minutes before the break when Pirlo was denied a second goal with another stunning free-kick, this time seeing his curling effort hit the bar.
Pegolo came to Siena's rescue in the 44th minute, saving well from Marchisio's curling free-kick to keep the hosts only one down - and moments later they were level.
Angelo provided the cross from the right wing and Calaio directed a neat header past Gianluigi Buffon to send the teams in at half-time all square.
Juve started the second half strongly, Arturo Vidal's blast brilliantly kept out by Pegolo and Mirko Vucinic curling inches wide before Giovinco's effort was cleared off the line by Alessandro Rosina and Pegolo got down well to frustrate Vidal.
Siena too had their chances, though. Rosina's right-wing cross was diverted wide from close range by Ribair Rodriguez while Calaio and Rosina also both nodded wide when well placed.
Juve showed the hosts how it should be done in the 85th minute by ruthlessly snatching the victory, Giovinco's left-wing cross headed by Giorgio Chiellini to Marchisio, whose sweet right-footed volley gave Pegolo little chance.
To their credit, Siena, who have picked up only two points all season, did not give up and could have grabbed a second equaliser in stoppage time, but Buffon was in the right place to keep out Massimo Paci's header from Alessio Sestu's right-wing cross.