Karaiskakis was born in a monastery near the village of Skoulikaria close to Arta. His father was the armatolos of the Valtos district, Dimitris Iskos or Karaiskos, his mother Zoe Dimiski and cousin of Gogos Bakolas, captain of the armatoliki of Radovitsi. He was of Sarakatsani descent. At a very early age he became a klepht in the service of Katsantonis, a famous local Agrafiote brigand captain. He excelled as a klepht — agile, cunning, brave and reckless — and rose quickly through the ranks, eventually becoming a protopalikaro, or lieutenant. At the age of fifteen he was captured by the troops of Ali Pasha and imprisoned at Ioannina, where close to Ali Pasha he learned Albanian. Ali Pasha, impressed by Karaiskakis’s courage and intelligence, and sensing his worth as a fighter, released him from prison and put him in the care of his personal bodyguards. He served as a bodyguard to Ali Pasha for a few years, before losing favour with the Ottoman warlord and fleeing into the mountains to continue his life as a klepht.
During the early stages of the war, Karaiskakis served in the army of Ali Pasha in his war against the Ottomans. After the defeat of Ali Pasha, in 1822, the Ottomans made him armatolos of Agrafa, but he soon broke with them and joined the Greek case. Karaiskakis served in the militia in the Morea, where he participated in the intrigues that divided the Greek leadership. Nonetheless, he recognized the necessity of providing Greece with a stable government and was a supporter of Ioannis Kapodistrias who would later become Greece's first head of state. Karaiskakis's reputation grew during the middle and latter stages of the war. He helped to lift the second siege of Missolonghi in 1823, and did his best to save the town from its third siege in 1826. That same year, he was appointed commander-in-chief of the Greek revolutionary forces in Rumeli, achieving a mixed response: while failing to cooperate effectively with other leaders of the independence movement or with the foreign sympathizers fighting alongside the Greeks, he gained some military successes against the Ottomans. His most famous victory was at Arachova, where his army together with other revolutionary leaders, crushed a force of Turkish and Albanian troops under Mustafa Bey and Kehagia Bey. Victories such as the one at Arachova were especially welcome amid the disasters that were occurring elsewhere. In 1827, Karaiskakis participated in the failed attempt to raise the siege of Athens, and attempted to prevent the massacre of the Ottoman garrison stationed in the convent of Saint Spyridon in Piraeus. He was killed in action on his Greek name day, 23 April 1827, after being fatally wounded by a rifle bullet during the Battle of Phaleron. According to Karaiskakis's expressed desire to be buried on the island of Salamis when he died, he was buried at the church of Saint Dimitrios on Salamis.
Karaiskakis was married to Engolpia Skylodimou, and had three children: daughters Pinelopi and Eleni, and the only son Spyridon. Sitsa Karaiskaki, a writer of the Interwar period, known for her pro-nazi beliefs, was also his descendant. She left Greece for Vienna with other collaborators after the Axis withdrawal in 1944, but returned later.
