Massimiliano Allegri's charges began confidently against the Blucerchiati, calmly stringing passes together and seeking to exploit any potential weaknesses in the opposition midfield.
Juve were making headway down the flanks but could not find the final touch, but the complexion of the game changed when Miralem Pjanic went off injured just before half time.
Allegri opted to bring on Douglas Costa, switching to a 4-2-4 formation in the process, and within one minute of the swap, the Brazilian delivered the cross which led to Mandzukic volleying Juve ahead.
From then on it was largely one-way traffic, as Costa's substitution continued to reap dividends with surges down the flank and deliveries which struggled to be dealt with by the Sampdoria back line.
Indeed, Costa went on to secure a hat-trick of assists, providing the cross for Benedikt Howedes to finish with a powerful diving header - the German's first goal in Serie A - on the hour mark.
On 75 minutes, the 27-year-old weaved his way into the Sampdoria penalty area from the right before cutting the ball back to Khedira, who calmly prodded past Viviano for goal number three.
Juve had few problems keeping tight at the other end and the final whistle heralded a routine win for the Old Lady, firmly in pole position for the Scudetto with just six games left to play.
JUVENTUS (4-3-3): Buffon; Howedes, Rugani, Chiellini, Asamoah; Khedira (Sturaro 81'), Pjanic (Costa 43'), Matuidi; Cuadrado, Dybala (Bentancur 66'), Mandzukic
SAMPDORIA (4-3-1-2): Viviano; Sala, Silvestre, Ferrari, Regini; Barreto (Verre 82'), Torreira, Praet; Ramirez (Caprari 61'); Quagliarella (Kownacki 46'), Zapata