The high genetic diversity of hepatitis C virus (HCV) complicates effective vaccine development. We screened a cohort of 435 HCV-infected individuals and found that 2%–5% demonstrated outstanding HCV-neutralizing activity. From four of these patients, we isolated 310 HCV antibodies, including neutralizing antibodies with exceptional breadth and potency. High neutralizing activity was enabled by the use of the VH1-69 heavy-chain gene segment, somatic mutations within CDRH1, and CDRH2 hydrophobicity. Structural and mutational analyses revealed an important role for mutations replacing the serines at positions 30 and 31, as well as the presence of neutral and hydrophobic residues at the tip of the CDRH3. Based on these characteristics, we computationally created a de novo antibody with a fully synthetic VH1-69 heavy chain that efficiently neutralized multiple HCV genotypes. Our findings provide a deep understanding of the generation of broadly HCV-neutralizing antibodies that can guide the design of effective vaccine candidates. Display omitted •Screening identified individuals with exceptional HCV Ab responses•Isolated broad and potent HCV-neutralizing Abs from elite neutralizers•Identified genetic antibody features associated with potent HCV neutralization•Designed de novo HCV Ab by machine learning that neutralized multiple HCV genotypes Broadly neutralizing antibodies (bNAbs) can protect from HCV infection, but little is known about their development and specific characteristics. Weber, Potthoff et al. isolated potent HCV bNAbs from individuals with exceptional HCV antibody responses and determined the genetic requirements for high neutralizing activity. Based on these data, they computationally designed a de novo antibody that efficiently neutralized multiple HCV genotypes.