Debbie Makki, 55, died in Greater Manchester in the early hours of Sunday morning, two days after she was rushed to hospital while "struggling at home" in isolation from family, including her grandchildren, due to the coronavirus lockdown, a statement said.
She "hadn't been the same" since her son Yousef, 17, was fatally stabbed in affluent Hale Barns, Cheshire, on March 2, 2019, and she "never found peace" after the boy who knifed him in the heart was cleared of murder and manslaughter.
The Makkis, from Burnage, Manchester, suffered another tragedy when family friend Aya Hachem, 19, was killed in a drive-by shooting while out buying groceries for her family in Blackburn, Lancashire, on May 17.
A Makki family statement said "at least you are with Yousef now", adding: "Mum died with a broken heart & we knew she wanted justice for Yousef & I promise you mum we won't give up until we get it for you."
In a statement, Mrs Makki's daughter, Jade Akoum, said the grief of losing a son and the family's "uphill battle" for justice had taken a considerable toll on her mother, and family members could not be with her in her final moments.
The family has been calling for a full inquest into Yousef's death.
In October, Ms Makki gave a speech at an anti-knife crime summit in Manchester.
Ms Akoum said: "My mum's mental and physically health had deteriorated dramatically over the past year and she hadn’t been the same since Yousef was murdered.
"Her heart was broken and the spark in her eyes had gone.
"The toll of losing Yousef was colossal, but the injustice and the constant uphill battle we had to fight meant she never found peace.
"There have been a lot of false promises to our family, beacons of hope from individuals that have amounted to nothing.
"I want to assure everyone that we will get to the bottom of this.
"Not only have these awful people taken Yousef, they have worn my mum down and taken her too.
"My mum was the strongest, bravest lady I have ever met and we will miss her dearly.
"We want to thank everyone who has supported us throughout and will continue to do so."
Another statement, on behalf of the Makki and Akoum families, said: "It is with a broken heart that we have to share this devastating news: our beloved Mum and Nana, so loved by everyone who knew her, died in the early hours of this morning.
"She was rushed to hospital via ambulance two days ago after struggling at home.
"The doctors told us she was critical. She was not strong enough to fight.
"Lockdown isolated my mum from her Grandchildren who kept her going and she had too much time to think about the loss of Yousef - and the stark injustice and inhumane treatment of our family that followed.
"She wondered why the the families of the boys involved in Yousef’s death have never contacted her and how they could be so cruel.
"It kept her awake most nights - she literally never slept.
"We were unable to be with her in her last moments, just as we were unable to be with Yousef - but they are together now which brings us some comfort.
"Our world has fallen apart all over again and we are all in complete shock."
Ms Akoum also tweeted: "24th Of May at 4am my beautiful strong mum Debbie Makki peacefully passed away.
"God rest your soul, at least you are with Yousef now, we told him we needed you here a bit longer but you had to be together!
"We love you so so much, i promise we will keep fighting for justice."
A further statement on Facebook said: "We love you so so much, I didn't think my heart could take any more pain and loss and grief.
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