He belonged to the poorer nobility, and first served under Lucchino Visconti in Lombardy, but within a year he entered the service of Andrew, King of Naples, who was assassinated in September 1345. In the autumn of that year he set out for the East in the French army. After the Battle of Smyrna in 1346 he was made a knight, and when the French army was disbanded he made his way to Jerusalem. He realized the advantage which the discipline of the Saracens gave them over the disorderly armies of the West, and conceived the idea of a new order of knighthood, but his efforts proved fruitless. The first sketch of the order was drawn up by him in his Nova religio passionis (1367-1368; revised and enlarged in 1386 and 1396). From Jerusalem he found his way in 1347 to Cyprus to the court of Hugo IV, where he found a kindred enthusiast in the king's son, Peter of Lusignan, then count of Tripoli; but he soon left Cyprus, and had resumed his career as a soldier of fortune when the accession of Peter to the throne of Cyprus (Nov. 1358) and his recognition as king of Jerusalem induced Mézières to return to the island, probably in 1360, when he became chancellor.
He came under the influence of the pious legate Peter Thomas (d. 1366), whose friend and biographer he was to be, and Thomas, who became patriarch of Constantinople in 1364, was one of the chief promoters of the crusade of 1365. In 1362 Peter of Cyprus, with the legate and Mézières, visited the princes of western Europe in quest of support for a new crusade, and when the king returned to the east he left Mézières and Thomas to represent his case at Avignon and in the cities of northern Italy. They preached the crusade throughout Germany, and later Mézières accompanied Peter to Alexandria. After the capture of this city he received the government of a third part of it and a promise for the creation of his order, but the Crusaders, satisfied by the immense booty, refused to continue the campaign.
In June 1366 Mézières was sent to Venice, to Avignon and to the princes of western Europe, to obtain help against the Saracens, who now threatened the kingdom of Cyprus. His efforts were in vain; even Pope Urban V advised peace with the sultan. Mézières remained for some time at Avignon, seeking recruits for his order, and writing his Vita S. Petri Thomasii (Antwerp, 1659), which is invaluable for the history of the Alexandrian expedition. The Prefacio and Epistola, which form the first draft of his work on the projected order of the Passion, were written at this time.
Mézières returned to Cyprus in 1368, but was still at Venice when Peter was assassinated at Nicosia at the beginning of 1369, and he remained there until 1372, when he went to the court of the new pope Gregory XI at Avignon. He occupied himself with trying to establish in the west of Europe the feast of the Presentation of the Virgin, the office of which he translated from Greek into Latin. In 1373 he was in Paris, and he was thenceforward one of the trusted counsellors of Charles V, although this king had refused to be dragged into a crusade. He was tutor to his son, the future Charles VI, but after the death of Charles V he was compelled, with the other counsellors of the late king, to go into retirement.
He lived thenceforward in the convent of the Celestines in Paris, but nevertheless continued to exert an influence on public affairs, and to his close alliance with Louis of Orleans may be put down the calumnies with which the Burgundian historians covered his name. When Charles VI freed himself from the domination of his uncles the power of Mézières increased. To this period of his life belong most of his writings. Two devotional treatises, the Contemplatio horae mortis and the Soliloquuum peccatoris, belong to 1386-1387. In 1389 he wrote his Songe du Vieil Pelerin, an elaborate allegorical voyage in which he described the customs of Europe and the near East, and advocated peace with England and the pursuit of the Crusade. His Oratio tragedica, largely autobiographical, was written with similar aims. In 1395 he addressed to Richard II of England an Epistre pressing his marriage with Isabella of Valois. The Crusade of 1396 inspired Mézières with no enthusiasm. The disaster of Nicopolis on September 28 1396 justified his fears and was the occasion of his last work, the Epistre lamentable el consolatoire, in which he put forward once more the principles of his order as a remedy against future disasters.
Some of his letters were printed in the Revue historique (vol. xlix.); the two épistres just mentioned in Kervyn de Lettenhove's edition of Froissart's Chroniques (vols. xv. and xvi.). The Songe du vergier or Somnium viridarii, written about 1376, is sometimes attributed to him, but without definite proofs.