On 12 October 1641, Luigi Mattei led 12,000 infantry and up to 4,000 cavalry against the fortified town. The pope's forces were met by a contingent of 40 troops guarding a bridge leading to the town; a short burst of cannon-fire resulting in a single death was enough to prompt capitulation. Castro, and several other small towns nearby, surrendered. Fabrizio Savelli, though, proved to be an unenthusiastic commander. The army was split into three and the Pope's nephew, Taddeo Barberini, replaced Savelli as Generalissimo, arriving with one contingent in the papal city of Ferrara on 5 January 1642. On 11 January the opera L'Armida, by Barberini house composer Marco Marazzoli, was presented in his honour and Marazzoli composed a work Le pretensioni del Tebro e del Po to commemorate recent events.
On 13 January, Urban excommunicated Odoardo and rescinded his fiefdoms (which had been granted by Pope Paul III – Odoardo's great-great-great-grandfather – in 1545). Odoardo countered with a military march of his own, this time on the papal state itself and his forces were soon close enough to threaten Rome. But Odoardo faltered and the Pope was able to fortify Rome and raise a new army - this time 30,000 troops; enough to drive the Duke back to his own territory. Odoardo forged alliances with the Venice, Modena, and Tuscany which was under the command of his brother-in-law, Ferdinando II de' Medici, Grand Duke of Tuscany.
At first, Pope Urban threatened to excommunicate anyone who helped Odoardo, but Odoardo's allies insisted their conflict was not with the papacy, but rather with the Barberini family (of which the Pope happened to be a member). When this failed, the Pope attempted to call on old alliances of his own and turned to Spain for assistance. But he received little help as Spanish forces were fully occupied by the Thirty Years' War. As it was, most of the troops fighting on the side of the papacy were French, most of those fighting for the Dukes were German.
Exasperated, the Pope increased taxes and raised additional forces and the war continued with Cardinal Antonio Barberini (Taddeo's brother) finding success against the Venetians and Modenese. But Papal forces suffered significant defeats in the area around Lake Trasimeno at the hands of the Tuscans (the Battle of Mongiovino). Fighting in the style typical of 17th-century Europe, by the latter half of 1643 neither side had made significant ground, though both sides had spent significant amounts of money perpetuating the conflict. It has been suggested that Pope Urban and forces loyal to the Barberini spent some 6 million thalers during the 4 years of the conflict that fell within Pope Urban's reign.
The papal forces suffered a crucial defeat at the Battle of Lagoscuro on 17 March 1644 and were forced to surrender. Antonio Barberini was almost captured; saved, "only by the fleetness of his horse". Peace was agreed to in Ferrara on 31 March.
Under the terms of the peace, Odoardo was readmitted to the Catholic Church and his fiefdoms were restored to him. Grain shipments from Castro to Rome were once again allowed and Odoardo was to resume payments to his Roman creditors. This peace settlement concluded the First War of Castro and was widely considered a disgrace to the papacy, which was unable to impose its will through use of military force. Urban is said to have been so distressed that after signing the peace agreements he was overcome by a severe malady which stayed with him until his death.