Following the outbreak of the Greek War of Independence, Kasomoulis took part in the uprising in the region of Mount Olympus and Chalcidice, where he co-operated with the chieftain Diamantis Nikolaou. His father, who in the meantime had moved to Naoussa, was killed there during the sack of the town by the Ottomans in April 1822. Following the suppression of the revolution in Macedonia, Kasomoulis went to Thessaly with a band of men from Siatista, where he joined the forces of Nikolaos Stournaris and Georgios Karaiskakis. In 1826 he took part in the Third Siege of Missolonghi, along with his brothers Dimitrios and Georgios. He composed the written decision for attempting a final sortie, and was responsible for coordinating the actions of the various detachments participating in the sortie. During the sortie, his brother Dimitrios was mortally wounded.