It was a period of intense religious conflict in the Rhineland, and the life of Antonius Hulsius would be deeply impacted by the Thirty Years' War (1618–1648).

His mother, born Catharina von Venne, died in 1628 when the boy was just 13, after which he went to live with his elder brother, the young theologian-paster Wilhelmus Hülsius (Wilhelm Hüls: 1598–1659) at Wesel, some distance to the north.

[2] By 1636 the war had been underway for eighteen years, and the movements of large armies correlated with an increased frequency and intensity of plague.

[2][6] Hulsius remained in Geneva for approximately two years, during which, there are references to his having delivered his first sermons at the local German language church.

[2][3] Hulsius returned to the Netherlands during or shortly before 1640, and spent several years working at Leiden, Amsterdam and Groningen, having become in 1640 a backer of the so-called "Walloon church", which was a Protestant-Calvinist community, comprising mainly Huguenots and other Protestants who had moved from France and Catholic southern Flanders to the Netherlands, attracted by the Dutch reputation for religious tolerance.

[2] After a period based in Amsterdam he became minister to the francophone community in Breda, participating with particular devotion in the construction of their church building.

His robust championing of the "orthodox" wing of his church was on display, in particular, in his sustained attacks on the heterodox mysticist pietism of Jean de Labadie.

Nevertheless, as the intellectual currents in Protestant Theology departments moved on during the second half of the seventeenth century, he also became the target of intensifying criticism and satire from those who did not share his uncompromising religious approach.

[1][2][3] His final years were marked – and in the eyes of some "less conservative" commentators his reputation was scarred – by high-profile disputes against the covenanter from Franeker, Johannes Cocceius and the Cartesian controversialist, Abraham Heidanus.