Jeffries led the Cowboys in 2023 but was granted a release from his contract late last year while linked with the Knights job.
He fills the role left vacant by Ron Griffiths, who's shifted to the Knights' NSW Cup job after steering the women's side to consecutive championships.
Jeffries, who played lower-grade football with Newcastle before a career that included a lengthy spell in the Super League, has signed a three-year contract.
Along with the Cowboys, he has also coached the Indigenous All-Stars and Papua New Guinea womens' sides.
"Ben is an accomplished coach, with a proven track record in pathways programs," Newcastle's football director Peter Parr said in a statement.
"This role requires a multi-faceted skill set, as we continue to strive for success on the field, in conjunction with further developing a gold-standard pathways program.
"Ben provides us with what we were looking for and we have no doubt the Knights' NRLW program will continue to grow under his coaching."
Jeffries' North Queensland outfit struggled in their first season in the NRLW, going 2-7 for an eighth-placed finish.
The club has yet to announce a replacement for Jeffries.
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