John Doukas Vatatzes, born in about 1192 in Didymoteicho, was probably the son of the general Basileios Vatatzes, Duke of Thrace, who died in 1193, and his wife, an unnamed daughter of Isaakios Angelos and cousin of the Emperors Isaac II Angelos and Alexios III Angelos. The Vatatzes family had first become prominent in Byzantine society during the Komnenian period and had forged early imperial connections when Theodore Vatatzes married the porphyrogennete princess Eudokia Komnene, daughter of Emperor John II Komnenos.
John Doukas Vatatzes had two older brothers. The eldest was Isaac Doukas Vatatzes (died 1261), who married and had two children: John Vatatzes (born 1215), who married to Eudokia Angelina and had two daughters: Theodora Doukaina Vatatzaina, who later married Michael VIII Palaiologos; and Maria Vatatzaina, who later married Michael Doukas Glabas Tarchaneiotes, military governor of Thrace.
A successful soldier from a military family, John was chosen in about 1216 by Emperor Theodore I Laskaris as the second husband for his daughter Irene Laskarina and as heir to the throne, following the death of her first husband, Andronikos Palaiologos. This arrangement excluded members of the Laskarid family from the succession, and when John III Doukas Vatatzes became emperor in mid-December 1221, following Theodore I's death in November, he had to suppress opposition to his rule. The struggle ended with the Battle of Poimanenos in 1224, in which his opponents were defeated in spite of support from the Latin Empire of Constantinople. John III's victory led to territorial concessions by the Latin Empire in 1225, followed by John's incursion into Europe, where he seized Adrianople.
John III's possession of Adrianople was terminated by Theodore Komnenos Doukas of Epirus and Thessalonica, who drove the Nicaean garrison out of Adrianople and annexed much of Thrace in 1227. The elimination of Theodore by Ivan Asen II of Bulgaria in 1230 put an end to the danger posed by Thessalonica, and John III made an alliance with Bulgaria against the Latin Empire.
In 1235 this alliance resulted in the restoration of the Bulgarian patriarchate and the marriage between Elena of Bulgaria and Theodore II, respectively Ivan Asen II's daughter and John III's son. In that same year, the Bulgarians and Nicaeans campaigned against the Latin Empire, and in 1236 they attempted a siege of Constantinople. Subsequently, Ivan Asen II adopted an ambivalent policy, effectively becoming neutral, and leaving John III to his own devices.
John III Vatatzes was greatly interested in the collection and copying of manuscripts, and William of Rubruck reports that he owned a copy of the missing books from Ovid’s Fasti (poem). Ruburck was critical of the Hellenic traditions he encountered in the Empire of Nicaea, specifically the feast day for Felicitas favored by John Vatatzes, which Risch suggests would have been the Felicitanalia, practiced by Sulla to venerate Felicitas in the 1st Century with an emphasis on inverting social norms, extolling truth and beauty, reciting profane and satirical verse and wearing ornamented "cenatoria", or dinner robes during the day.
In spite of some reverses against the Latin Empire in 1240, John III was able to take advantage of Ivan Asen II's death in 1241 to impose his own suzerainty over Thessalonica (in 1242), and later to annex this city, as well as much of Bulgarian Thrace in 1246. Immediately afterwards, John III was able to establish an effective stranglehold on Constantinople in 1247. In the last years of his reign Nicaean authority extended far to the west, where John III attempted to contain the expansion of Epirus. Michael's allies Golem of Kruja and
Theodore Petraliphas defected to John III in 1252.
John III died in Nymphaion in 1254, and was buried in the monastery of Sosandra, which he had founded, in the region of Magensia.