The study was conducted in Tehulederie, Kalu, and Dessie Zuria districts of South Wollo Zone, Amhara, Ethiopia, to assess the current beekeeping production system with available opportunities and challenges facing the beekeeping subsector. The districts were purposively selected based on potential and accessibility and then stratified into lowland, midland, and highland. In total, 135 beekeepers, of which 126 were males and 9 were females, were interviewed using a pretested semistructured questionnaire. The result revealed that beekeeping is actively practiced by the community regardless of age and sex. Three beekeeping production systems, that is, traditional, transitional, and movable frame hive, have been identified, accounting for 80%, 4%, and 16%, respectively. More than 80% of total bee colonies are managed being placed in the backyard. Besides, the study indicated that about 79% of the beekeepers keep bees primarily for income generation and home consumption. According to this study, the average bee colony holding size is 5.13 per a beekeeper. Also, this study identified that the swarm catching method is the major source of bee colony accounting for more than 45% to start beekeeping and 76% to increase existing colony number. Bee colony decline, absconding and swarming, honeybee pests and predators, and lack of training and extension were identified as major beekeeping challenges in the study areas. This study identified the beekeeping production system, opportunities, and challenges of the study areas and has significantly contributed to our knowledge and identified lack of extension and training as intervention areas. Therefore, practical beekeeping training and extension should get primary emphasis to combat the existing challenges.