In 1494 he followed the king in war for the Kingdom of Naples, taking part in the latter city's capture in 1495, as well as in the battle of Fornovo (1498) against the Italian League, which allowed the French army to retreat in their homeland.

After Charles' death, La Palice accompanied the new King, Louis XII, in the campaign for Milan, which the French captured in 1499.

After Gaston de Foix's arrival to Italy, La Palice was put under him, successfully relieving Bologna from the Spanish's siege.

Returning to France, he was sent to the Pyrenees to rescue John III of Navarre, but soon he was diverted to Thérouanne, then the last French possession in the Artois, to counter the English troops.

La Palice, under the command of Marshal Aubigny, took part to the invasion of Piedmont and the capture of Prospero Colonna in Villafranca, and was one of Francis' lieutenants at the battle of Marignano.

La Palice was sent at Calais as negotiator of the peace with Charles V. As the participants did not reach an agreement, he returned to Italy as military leader under Marshal Lautrec, commanding the French main line at the battle of Bicocca (1522), in which he was defeated by Colonna.

The coinage originates from la Palice's epitaph, which reads[1][2] These words were misread (accidentally or intentionally) as "...il ſerait [serait] encore en vie" ("...he would still be alive"), where the long s favours the confusion.