Natasha Jackson, now 23, has been awarded £7m after errors at Sharoe Green Hospital, Preston, resulted in her developing cerebral palsy.
It follows a £6m payout for her brother Patrick, 22, who also has the condition, awarded in 2010.
The NHS Litigation Authority said the compensation would fund their care.
Legal action was brought against the now-defunct North West Strategic Health Authority, which was responsible for Sharoe Green at the time.
Both Natasha and Patrick were left severely disabled after errors during their deliveries at the hospital, which closed in 2004.
Their mother, Paula McKay, fought lengthy legal battles to secure compensation for her children, who both require specialised accommodation and equipment.
Ms McKay, from Leyland, Lancashire, said it had been "devastating" to learn her daughter had cerebral palsy shortly after she was born.
It "ripped her heart out", she said, when Natasha's younger brother was also diagnosed with the condition at 18 months old.
"The first time was bad enough but we were absolutely devastated for it to happen a second time," she said.
Lawyer Olivia Scates, who represented the Jacksons, said it was "unprecedented" for two children from the same family to suffer brain damage as a result of clinical negligence.
Ms McKay said the settlements had reassured her both children would be taken care of after she died.
"I was desperate not to see them end up reliant on social services care in a home that was not appropriate for them," she said.
Ms McKay said the payout "wasn't like winning the lottery" as it has to last both of her children for the rest of their lives.
"The money is all budgeted into different pots - transport, staff, training, accommodation and holidays for Natasha and Patrick," she said.
The NHS Litigation Authority said: "Compensation has been agreed with the family, which will assist in meeting the claimant's current and future care needs for life."
Two siblings left brain damaged from birth have been awarded multimillion-pound payouts in "unprecedented" clinical negligence cases.