There is currently a limited understanding of adolescent sibling relationships where Autism Spectrum Disorder (ASD) is present. This research gap remains despite preliminary findings suggesting that neurotypically developing (NTD) siblings undertake extra caregiving responsibilities and experience differential treatment from family members. Using a Family Systems approach, this qualitative study investigated NTD adolescent sisters’ roles and responsibilities for their younger adolescent brother with ASD from the perspectives of 11 family members (including NTD sisters, brothers with ASD, mothers, and fathers). Findings indicate the sisters undertook various caregiving roles and responsibilities, particularly at school, which had both positive and negative influences on the family system. Additionally, sisters perceived they undertook unfair household responsibilities, received reduced parental attention, and desired both distance from and engagement with their families. These perceptions varied amongst other family members. Implications of these findings and strategies for best supporting adolescent NTD siblings are discussed.