The opioid overdose crisis primarily driven by potent synthetic opioids resulted in more than 500,000 deaths in the US over the last 20 years. Though naloxone, a short acting medication, remains the primary treatment option for temporarily reversing opioid overdose effects, alternative countermeasures are needed. Monoclonal antibodies present a versatile therapeutic opportunity that can be tailored for synthetic opioids and that can help prevent post-treatment renarcotization. The ultrapotent analog carfentanil, is especially concerning due to its unique pharmacological properties. With this in mind, we generated a fully human antibody through a drug-specific B cell sorting strategy with a combination of carfentanil and fentanyl probes. The resulting pan-specific antibody was further optimized through scFv phage display. This antibody, C10-S66K, displays high affinity to carfentanil, fentanyl, and other analogs, and reversed carfentanil-induced respiratory depression. Additionally, x-ray crystal structures with carfentanil and fentanyl bound provided structural insight into key drug:antibody interactions.