At first she was a leader of one of the groups of dissident Jedi led by Sora Bulq who did not return to Coruscant at the beginning of the Clone Wars, believing that the Galactic Republic was too corrupt to be saved.
She joined with the other three leaders—K'Kruhk, Rhad Tarn, and Mira—to meet with Sora Bulq on the moon of Ruul. Mace Windu also went to meet them on Ruul. During an assassiation attempt, Jeisel had to kill Tarn after the Dark Jedi Asajj Ventress turned him to the dark side. With the help of Windu, she and K'Kruhk escaped, as Tarn and Mira were both dead.
After Bulq's defection to the Confederacy of Independant Systems, Sian Jeisel rejoined the Republic and led troops in many battles. On one mission, Sian was one of several Jedi who were on the Republic Troopship VCD987. While en route to the planet Drongar, VCD987 came under attack by an immensely superior Separatist force and sustained massive damage to its engines—with the engines no longer functioning, Separatist troops, under the leadership of Count Dooku, boarded the ship and cornered Jedi Masters Tsui Choi, Kai Justiss and Sian Jeisel. In an attempt to appear merciful and thus sway Jedi to the Separatist cause, Dooku allowed the captured Jedi to go free, instead choosing to only kill the clones which were aboard the ship instead.
Towards the end of the war, she fought as a Jedi General in the Siege o Saleucami. Her relationship with the other Jedi Masters was difficult: she didn't trust Quinlan Vos, but she mourned the death of Oppo Rancisis. She fought well during the siege along with A'Sharad Hett and K'Kruhk, to whom she was very close.
In the final days of the Clone Wars, Jeisel, along with K'Kruhk, landed in a damaged shuttle at a Jedi academy. It was there that Order 66 was received by the troops who accompanied them, but K'Kruhk sensed their intent only seconds before they opened fire on the younglings. Jeisel helped the students escape by blocking the blaster shots along with Jedi Du Mahn, until K'Kruhk had herded the students outside to their shuttle. He told Jeisel to come along with them, but she declined, saying someone had to hold the clone troopers off and that K'Kruhk was the better pilot. Soon, Jeisel detonated one of the troopers' thermal detonators with the Force, sacrificing herself to allow K'Kruhk and the students to escape.
Despite this, rumors of her survival would continue throughout the years, and ended up in the history work of Voren Na'al written in 35 ABY.