Background Avian Influenza is a highly contagious viral infection that mainly affects domesticated birds. On June 21, 2018, the Kwahu-West Municipal Veterinary Office was notified of sudden deaths of birds on a poultry farm. Seven days later, a second farm sited 100 meters from the index case-farm also recorded bird deaths. We investigated to confirm the causative agent, identify its source, and implement control measures. Methods We conducted a survey of six poultry farms and human contacts of affected farms in Nkawkaw. A suspected case-farm of HPAI was any farm in Nkawkaw with sudden death of bird(s), with or without clinical signs of HPAI from June 1 to July 10, 2018. Six bird carcasses were collected on affected farms for laboratory analysis. We interviewed owners of affected farms and assessed the farm environments, as well as clinical status of human contacts. Results A total 2,280 birds were affected on two adjacent farms. HPAI-H5N1 was confirmed for all samples investigated. The index case-farm with 1,438 birds, reported 30 bird deaths on June 16, 2018, 24 hours after receiving a consignment of birds from an HPAI-H5N1 confirmed farm in a neighboring region of Ghana. The second case-farm recorded bird deaths 7 days later. Both farms operated aluminum sheet-roofed metallic mesh pens without fencing. Beddings in pens were not regularly changed. Four poultry farms located within an 6km radius of the affected farms did not report sick or dead birds. All twenty-three human contacts were asymptomatic of flu, after 14-days follow-up. Conclusions This HPAI-H5N1 outbreak was likely imported through the introduction of birds from a neighboring region due to lax livestock movement regulations, and poor biosecurity measures on farms. Disinfection and depopulation exercises effectively controlled the outbreak. We recommend strict implementation of biosafety measures on farms and at entry points in the district