Background Gastrointestinal helminth parasite infection is a major influencing factor against profitability of working equines all over the world. Objectives A study was conducted from October 2016 to May 2017 in and around Hosaena to determine the efficacy of benzimidazole (BZ) and avermectin (AVM) chemical groups against strongyle nematodes in working donkeys. Methods A total of 230 donkeys from Hosaena, Soro, Anlemo, and Gombora were randomly allocated into 5 groups of 46 donkeys in each group. All groups, except group 1 (control), were treated with ivermectin 1%, ivertong 10%, fenbendazole, and Fenacure 750 mg, respectively. Fecal samples were collected perrectally before treatment (day 0) and after treatment (day 14), and an egg per gram (EPG) value of >200 was used as a cutoff for inclusion to assess the efficacy of anthelmintics. Results Accordingly, the study revealed that AVM was effective against strongyle nematodes of donkeys with the mean fecal egg count reduction (FECR) of 100% in three study areas and 97.2% in one study area, respectively, whereas BZ resistance was suspected in the areas where the drug was tested, with the mean FECR of less than 94% in the three study areas. The study also revealed that 73% of the donkeys were affected with a severe degree of strongyle infection as determined by EPG, while 10.4% of donkeys were affected with a mild degree of Parascaris equorum infection. Conclusions The findings of the present study are expected to serve as baseline data for future investigations and control actions to design realistic control programs to minimize factors that favor emergence of anthelmintic resistance and improve the overall health of the donkeys. Thus, further detailed studies are needed to determine the factors that reduce anthelmintic efficacy and increase anthelmintic resistance in donkeys.