Marchella Brett-Pierce weighed 18 pounds when she died in September.
The medical examiner says Marchella suffered from child abuse syndrome, including acute drug poisoning, blunt impact injuries, malnutrition and dehydration.
Brooklyn District Attorney Charles Hynes said the former Administration for Children's Services workers didn't do enough to help Marchella.
A caseworker and supervisor who resigned from ACS in October have been charged with criminally negligent homicide and official misconduct, and her grandmother was indicted on a manslaughter charge, the prosecutor said.
"ACS has a single overarching mission to protect abused and neglected children in New York City. Our staff live up to this difficult and heart-breaking challenge every day," the child welfare agency said in a statement. "Yet when we fail, it can be with tragic results, which we try to learn from and make adjustments. ... When staff have failed to carry out their basic responsibilities, ACS will and does take appropriate action.
"The particular merits of this criminal case aside, we are very concerned that today's indictments of social work staff may have the opposite effect from what's intended because it may discourage excellent, idealistic individuals from taking jobs helping our society's neediest and most vulnerable children," the agency said.
Marchella's mother told police that she found her daughter's cold and unconscious body on Sept. 2 and tried to resuscitate her before calling 911. The girl was born with underdeveloped lungs, had serious trouble breathing and had a breathing tube in her throat, authorities said. She had been hospitalized in the months before her death.
Marchella's mother, Carlotta Brett Pierce, was previously indicted on murder and other charges, and has said she is innocent.
However, now most of the attention is focused on ACS and the former workers who now sit in jail.
Their defense attorneys and union representatives see this as an unfortunate political move by the DA with freedom and future hanging in the balance.
"What the Brooklyn district attorney has done is indicted our entire profession. Anyone who does direct social services can be caught in the same position," said Social Service Employee Union President Faye Moore.
"If his focus is on ACS then why has he asked that Chereece Bell be kept at Riker's Island and away from her children tonight? Why? Why are they making scape goats of these two people?" said Joshua Horoqitz, Bell's defense attorney.
Bell's attorney says his client has two children ages 10 and 3.
She has never been in trouble with the law.
Marchella's death was the latest in a line of troubles linked to the agency and harkened comparisons to the 2006 case of Nixzmary Brown, a 7-year-old New York City girl who died of abuse and malnourishment.
Earlier this week, a man was charged with assault and reckless endangerment after his girlfriend's 17-month-old foster child was found unconscious and badly beaten, possibly with a bat. Kymel Oram suffered bruising, fractured ribs, a lacerated liver and a bruised spleen. He remained in critical condition, though a criminal complaint against the suspect, Kysheen Oliver, says the toddler was likely to die.