Objective To evaluate the efficacy of albendazole (ABZ) and pyronaridine (PND) for the treatment of cystic echinococcosis (CE) in sheep. Methods B-mode ultrasonography was performed in sheep from the central Tianshan Mountains regions in Xinjiang Uygur Autonomous Region, and 18 sheep with typical CE characteristics and comparable prevalence were selected, and randomized into the control group, the ABZ group and PND group using a completely randomized design. Sheep in the ABZ group were fed baits containing ABZ (0.4 g ABZ in 1 g feed bait), and sheep in the PND group were fed baits containing PND (0.2 g PND in 1 g feed bait), while sheep in the control group were fed drug-free feed baits. Drugs were administered continuously for 30 days, followed by a 30-day observation period after drug discontinuation. Whole-liver scans were performed on sheep with CE before dosing and 30 days after drug discontinuation, and cyst size was recorded. Sheep hearts, livers, spleen, lungs, and kidneys were collected and weighed 30 days after drug discontinuation. Whole blood samples were collected for routine blood tests and blood biochemistry analysis. Liver cysts were sampled, and classified into fertile cysts, infertile cysts, and calcified cysts based on the cyst appearance and its contents. The number and weight of different types of cysts were recorded. Hepatic tissues were prepared into paraffin-embedded sections, subjected to hematoxylin-eosin (HE) staining for pathological examinations, and evaluated for scoring of inflammatory cell infiltration. All statistical analyses were performed using the software IBM SPSS Statistics 20. Multiple comparisons were conducted using one-way analysis of variance or nonparametric tests, while intergroup comparisons of cyst types were assessed using chi-square test. Results B-mode ultrasonography measured no significant difference in the diameter of liver cysts among the control group [(2.86 ± 0.94) cm], ABZ group [(2.58 ± 0.83) cm], and PND group [(2.65 ± 0.81) cm] prior to oral administration (F = 0.090, P > 0.05). The diameters of cysts were (0.41 ± 0.30) cm in the ABZ group and (0.85 ± 0.24) cm in the PND group 30 days after drug discontinuation, which were significantly smaller than in the control group [(3.03 ± 0.42) cm] (F = 110.398, P < 0.01). The sheep liver weights were (0.98 ± 0.20), (0.74 ± 0.16), and (0.61 ± 0.30) kg in the control group, ABZ group, and PND group 30 days after drug discontinuation, respectively (F = 3.989, P < 0.05). There were no significant differences in routine blood and biochemical parameters among the control, ABZ, and PND groups (all P > 0.05). The gross cyst weights were (0.02 ± 0.05) kg and (0.05 ± 0.08) kg in the ABZ and PND groups 30 days after drug discontinuation, which were significantly lower than in the control group [(0.17 ± 0.06) kg] (F = 7.835, P < 0.01). The proportions of fertile cysts, infertile cysts, and calcified cysts were 63.16% (48/76), 17.10% (13/76), and 19.74% (15/76) in the control group, and 23.08% (12/52), 1.92% (1/52), and 75.00% (39/52) in the ABZ group, respectively (χ² = 39.439, P < 0.01), with reduced proportions of fertile and infertile cysts and an increased proportion of calcified cysts in the ABZ group. The proportions of fertile cysts, infertile cysts, and calcified cysts were 31.03% (18/58), 6.90% (4/58), and 62.07% (36/58) in the PND group, which showed significant differences relative to the control group (χ² = 25.083, P < 0.01), with an reduced proportion of fertile cysts and an increased proportion of calcified cysts in the PND group. The scores of inflammatory cell infiltration were 1.06 ± 0.25 and 1.50 ± 0.28 in the ABZ and PND groups 30 days after drug discontinuation, which were both significantly lower than in the control group (2.72 ± 0.44) (F = 39.780, P < 0.01). Conclusion Oral administration of ABZ or PND may reduce the number of fertile cysts in livers of sheep with CE and alleviate the severity of inflammatory cell infiltration, indicating that both chemicals are effective against sheep CE.