The Azzurri is unbeaten Group B leader on 10 points from four games as it approaches the halfway mark of the qualification campaign for the finals in Brazil.
Rallying from two goals down to clinch a 2-2 draw in a friendly with the World Cup host last week brought acclaim to the Azzurri, but Prandelli warned about the risks of lowering the guard against the zero-point host in Ta'Qali.
"Tuesday in Malta we have a crucial game for our qualification," Prandelli said. "It is an important game because when small teams meet Italy it is their game of the century.
"We must be very well prepared when we get there. Then, of course, our technical qualities are superior and we want the three points."
Prandelli has midfielder Daniele De Rossi, on target against Brazil, and forward Pablo Osvaldo suspended for the game in the Mediterranean island, plus defender Giorgio Chiellini out with injury.
Andrea Barzagli, who is Chiellini's defence companion at Juventus, agreed that concentration must be high against Malta, which lost 2-0 in Italy in September and crashed 6-0 at Bulgaria last tie out.
Bulgaria is now one point behind Italy, having already played its fifth game.
"After the good game with Brazil, the risk is going to Malta with the wrong attitude," Barzagli said. "The game will be tough. We must be as focussed as we can and build on the spirit we displayed against the Brazilians."
The match at the Ta'Qali stadium could offer scoring chances to Mario Balotelli, who levelled against Brazil with a great long-range effort to continue a scoring run of seven goals from the six games played with AC Milan since his late January transfer from Manchester City.
The 22-year-old's tally is currently of six games from 18 appearances with the Azzurri.
He was praised for his tactical discipline against Brazil and for the modesty he professed after the game.