Two superb 25-yard free-kicks from AC Milan midfielder Andrea Pirlo were enough to thwart a brave rearguard effort by Scotland in Milan.
Italy made the breakthrough their pressure deserved after 35 minutes.
Nigel Quashie forced Gianluigi Buffon into a fine save and Kenny Miller squandered a chance as the visitors came close to a second-half equaliser.
But Pirlo struck with another curler five minutes from the end to secure victory in the World Cup qualifier.
Running the Group Five leaders so close in the San Siro will have given some heart to Walter Smith in his first game as Scotland manager.
More than 10,000 Scotland fans left Milan in good voice, but the result leaves their side with only two points in their first four games.
Smith had named a formation with containment in mind, with Miller the only striker.
Hearts' Paul Hartley was handed a debut at the age of 28, while there was also a first start in midfield for Wigan Athletic's Lee McCulloch.
Everton defender David Weir completed his international comeback after a fall-out with previous boss Berti Vogts prompted his retirement in 2002.
The reshaped side started confidently, but Italy gradually dominated possession and long-range efforts by Francesco Totti and Alberto Gilardino forced goalkeeper Rab Douglas into confident catches.
Douglas produced a superb reaction save to turn a Antonio Cassano volley over the top after a chip through from Pirlo had found the striker unchallenged in the box.
Cassano had the ball in the net as Pirlo played it through again, but the flag had been raised.
But the breakthrough came on 35 minutes after Gary Caldwell and Steven Pressley combined to foul Gilardino.
Craig Gordon was preparing to take the place of the injured Douglas when Pirlo exploited the goalkeeper's immobility by curling the ball over the defensive wall and into the net.
Totti fired over from only eight yards out after Gilardino and Cassano had opened up the defence with a quick one-two.
But Scotland came close to equalising with their first real opportunity after 51 minutes.
Miller played a one-two with Quashie and the Southampton midfielder's powerful 15-yard drive was superbly turned wide by Buffon.
Barry Ferguson found Miller with an incisive through ball, but the Wolves striker fired straight at the goalkeeper's legs.
Scotland paid for those misses when Pirlo curled home another free-kick, this time leaving helpless Gordon's 6ft 4in frame.
Italy: Buffon, Bonera, Cannavaro, Materazzi, Chiellini, Camoranesi, Pirlo, Gattuso, Totti (De Rossi 72), Gilardino, Cassano (Toni 83).
Subs Not Used: Roma, Zaccardo, Grosso, Blasi, Esposito.
Booked: Cannavaro, Gattuso, Bonera.
Goals: Pirlo 35, 85.
Scotland: Douglas (Gordon 39), McNamara, Pressley, Weir, Naysmith, Caldwell, Hartley (McCann 76), Ferguson, Quashie, McCulloch, Miller (O'Connor 85).
Subs Not Used: Anderson, O'Neil, McCann, Webster.
Booked: Hartley, McNamara, Quashie, Pressley, Caldwell.
Ref: Kyros Vassaras (Greece).