Chelsea Yellowbird from the Samson Cree First Nation was shot and killed at her home on Sept. 5, 2011.
The house was next door to a house where her nephew, five-year-old Ethan Yellowbird, was shot dead while sleeping two months earlier.
RCMP say Randall Omeasoo, 21, of Hobbema was arrested Thursday and was being held in custody.
An Alberta Justice official said a third man, who has not been identified, has also been charged and a warrant has been issued for his arrest.
Police arrested Shelby Minde, 23, of Hobbema on a first-degree murder charge Wednesday after a two-year investigation.
Minde is to appear in Wetaskiwin provincial court Tuesday.
A court date for Omeasoo was pending.
The reserve, about 90 kilometres south of Edmonton, has struggled with drug- and gang-related violence over the years.
Three teens pleaded guilty to manslaughter last year in youth court for Ethan Yellowbird's death.
They admitted to taking turns firing a gun at a home, accidentally killing the boy.
(CKGY, The Canadian Press)
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