On 18 October 2017, Zahreddine was killed by a land mine explosion during operations against the Islamic State of Iraq and the Levant on Saqr island in Deir ez-Zor.

[15] As the Syrian Civil War escalated, Zahreddine became one of the most prominent and high-ranking members of the Druze community in Syria fighting for the government.

[16][2] Zahreddine was sent in early 2012 to Homs where the SAA offensive against rebel groups was culminating in the siege and Battle of Baba Amr, in which his troops surrounded the neighbourhood, blocked supply routes and shelled it.

On 21 February the government intercepted a call by famous war reporter Marie Colvin: "The [SAA] is simply shelling a city of cold, starving civilians".

[19] In a lawsuit filed in U.S. District Court for the District of Columbia, Colvin's family provided evidence that the Syrian government had tracked Colvin from Lebanon, triangulated the call to the Homs Media Center, and confirmed her location with a local informant, and that then, under orders from Maher al-Assad, the Homs units of the Syrian Republican Guard and Special Forces targeted her location, using a method known as bracketing, where multiple rockets were launched to either side, drawing closer with each round, before hitting it directly.

[23] Zahreddine and his son Yarob travelled to as-Suwayda in September 2015 in order to attend the funeral of Sheikh Wahid al-Balous, a Druze leader who had been a prominent anti-war activist.

[citation needed] In 2017, Zahreddine was added to a European Union sanctions list for his role in "violent repression against the civilian population, including during the siege of Baba Amr in February 2012.