Our study analyzed the ruminal fermentation and microbiome, hematological profile, and abomasal histopathology of lambs experimentally infected with a gastrointestinal nematode (GIN) and fed sainfoin pellets (SFPs; 600 g DM/d/animal) for 14 d. Twenty-four lambs infected with Haemonchus contortus were divided into two separated groups: animals fed meadow hay (control) and animals fed SFPs. The ruminal contents, fermentation parameters, and microbiome in vitro and in vivo were determined using molecular and microscopic techniques. Ruminal contents in the SFP group indicated smaller populations of Archaea (p Methanomicrobiales (p = 0.009), and lower methane concentrations in vitro (p = 0.046) and in vivo (p = 0.030) than the control group. The relative abundance of Butyrivibrio fibrisolvens quantified by real-time PCR was higher in the lambs with the SFP diet (p = 0.05). Haemonchosis affected the number of red blood cells of the lambs (p p = 0.004). The consumption of SFPs by GIN-infected lambs may affect ruminal methanogens and subsequently decrease methane emission without undesirable changes in the ruminal microbiome or the health of the animals.