After Venice defeated Visconti's attempt to invade Romagna in the Second Italian War, Venice was supreme hegemon of Northern Italy. It had puppets in the Pope, who now controlled Rome, Parma, and Milan itself. It's power extended to the East, where it possessed Cephallonia and Aydin, while it also dominated the Mediterranean islands. It even took Alexandria, giving it a huge economic sphere of influence.
While the Second War was originally an affair solely between Milan and the Italian coalition(Venice, Tuscany, and the Pope), it soon expanded. Hoping to take advantage of the chaos during the war, the Florentines invaded and annexed Pisa. The response was brutal, with Savoy, Genoa, Naples, and the Holy Roman Emperor forming a second coalition to fight off Tuscany. Venice also joined in by merit of having predicted Tuscany's aggression towards Pisa, and thus was in a perfect position to eliminate the Florentines.
The war ended with the Second Italian Coalition having made a grave mistake; through it's negligence, Venice seized 2/3 of Tuscany's territory in the form of Ancona and Pisa. This let Venice bloom into the hegemon of Italy, as Milan itself was soon absorbed into the Venetian-led forces.
As a result, Aragon and Naples made plans to destroy Venice, which threatened their position in the south of Italy. However, the Venetians caught evidence of this thanks to a plant in the Papal government, and launched a pre-emptive strike upon Naples.
The war was first between Venice and it's tributaries(the Pope, Cephallonia, Aydin) and Aragon-Naples. However, events prompted more powers to intervene. Siena, knowing that it would be doomed if Aragon was defeated, joined the Aragonese alliance. Tuscany remained neutral, as it was still devestated from the last war. When Corsica aligned with the Aragonese, Genoa joined it's Venetian rivals, hoping to reclaim Corsica.
From there, the fire spread outside Italy, with the Savoyards - who had invaded Milan beforehand and wanted a slice of Lombardia - declaring war upon Venice, wanting to curtail the growing Republic's power. Seeing opportunities in Savoy and wanting to press it's claims to Naples, the Angevins of Provence declared war upon Aragon. The Knights of St. John, knowing that Venice had designs on their strategic island, declared war upon Venice, hoping to flank them in the East.
The war stretched across Italy and the entire Mediterranean.
However, despite the odds, Venice would later triumph over the Aragonese. The Neopolitans would lose 2/3 of their territory, while Aragon would lose Sardinia, Malta and Sicily, while suffering the complete annihilation of it's fleet. The Third Italian War would pave the way to a pan-Italian state.