Louis proposed to renounce the Kingdom of Naples if Clement dethroned Joanna. After the pope refused, Louis departed for his second Neapolitan campaign in April 1350. He suppressed a mutiny that occurred among his mercenaries while he and his troops were waiting for the arrival of further troops in Barletta. While marching towards Naples, he faced resistance at many towns because his vanguards, which were under the command of Stephen Lackfi, had become notorious for their cruelty.

During the campaign, Louis personally led assaults and climbed city walls together with his soldiers, endangering his own life. While besieging Canosa di Puglia, Louis fell into the moat from a ladder when a defender of the fort hit him with a stone. He dove into a river without hesitation to save a young soldier who was swept away while exploring a ford upon his order. An arrow pierced Louis's left leg during the siege of Aversa. After the fall of Aversa to Hungarian troops on 3 August, Queen Joanna and her husband again fled from Naples. However, Louis decided to return to Hungary. According to the contemporaneous historian Matteo Villani, Louis attempted to "leave the kingdom without losing face" after he had run out of money and experienced the resistance of the local population.