Background: Regular whole-flock treatments and long-term use of similar anthelmintics have led to the development of anthelmintic resistance and widespread epidemics of nematodiasis in sheep. This study was performed to understand the prevalence of gastrointestinal nematodes in Ordos Merino sheep and evaluate the efficacy of currently used anthelmintics. Results: Between March 2017 and April 2019, a total of 4014 fresh fecal samples were collected from sheep, and fecal nematode eggs were qualitatively and quantitatively analyzed to understand the prevalence of sheep nematodiasis. The anthelmintic efficacy of currently used drugs was evaluated in naturally infected sheep. Severe infection by gastrointestinal nematodes was observed in the Ordos Merino sheep. The infection rates of the nematodes in 3 consecutive years were 84.3%, 36.9%, and 42.3%. Haemonchus contortus and Nematodirus sp. were the predominant nematode species, with infection rates of 84.3% and 65.6%, respectively, in 2017. Moreover, these species had acquired high resistance to ivermectin, doramectin, albendazole, and levamisole; the fecal egg count reduction percentages were 6.9%, 1.7%, 3.5%, and 79.0%, respectively, after a single administration. Nitroxynil and closantel showed strong anthelmintic efficacy against the predominant species Haemonchus contortus and other nematodes, but they had almost no effect on Nematodirus sp. Conclusions: The prevalence of gastrointestinal nematodes in Ordos Merino sheep and their resistance to commonly used anthelmintics were comprehensively evaluated, and the drugs with high efficacy against the predominant species were identified. The findings of this study will provide a good foundation for the appropriate use of anthelmintics.