Rabies is a widespread disease affecting all warm-blooded animals. In the current study the incidence and associated risk factors of rabies in humans and livestock were conducted in North-West Ethiopia with the aim of quantifying the incidence and associated risk factors of rabies. The prospective follow-up of rabid victims was recorded in seven districts of northwest Ethiopia for 18 consecutive months. Information from victims or bit animal owners was collected, entered into Excel, and were analyzed using Stata 17. A total of 393 rabid suspected cases were recorded during the follow-up period, of which 293 were bites by potentially rabid animals and 100 were probable rabid cases. Males to female ratio of human victims was (59.46% vs. 40.54%, respectively). Dog owners were more affected (62%) than non-dog owners. Dogs were the major animals (>96%) for exposure. The 5–14 years age group had the highest number of bites in human cases. The legs/feet (53.5%) were the most affected body part. The mortality rate of humans was 2.09 per 100,000 people per year during the current outbreak. People living in rural residences, males, and having dogs in the house were the main risk factors for exposure to rabies. Hence, rabies continues to pose a threat to humans and animals. The results of this research will provide a useful information for scientific communities and policy makers and governement health and veterinary professionals.