Piroplasmosis and trypanosomiasis are debilitating diseases of great economic impact on the equine industry of Latin America. Considering the lack of studies in the northeastern part of Colombia, this study aims to determine the clinical and epidemiological features associated with infection of the Babesia, Theileria, and Trypanosoma genera in horses from this geographical area. Two hundred and eighty horses from the Arauca, Meta, and Santander departments were molecularly analyzed for infection with Babesia caballi, Theileria equi, Trypanosoma evansi, and Trypanosoma vivax. Furthermore, clinical and epidemiological analyses were performed on the data sets. Molecular analysis showed 25.7% and 3.9% prevalence for T. equi and T. evansi, respectively, without positive animals for B. caballi and T. vivax. There were no differences in the prevalence of T. equi between departments, whereas T. evansi was detected exclusively in Santander. For T. equi, epidemiological analysis revealed a significant association between tick infestation and lack of vector control with molecular infection, whereas clinical analysis revealed a significant reduction in packed cell volume, red blood cells, and mean corpuscular volume in positive animals. Furthermore, molecular infection by T. evansi was associated with ecological characteristics in the Santander department. In conclusion, our analysis revealed a high infection rate by T. equi in horses from northeastern Colombia, which affects their clinical conditions. Control of ticks and treatment of symptomatic animals should be considered to reduce the economic impact of this industry.