Tick-borne diseases (TBD) occur in many temperate countries and are economically important in most tropical and subtropical areas, affecting dairy and beef cattle, as well as small ruminants. Four major tick-borne diseases have been detected in eastern and southern Africa: East Coast fever (ECF) caused by Theileria parva, Theiler 1904, anaplasmosis caused by either Anaplasma marginale, Theiler 1910, Anaplasma centrale, Theiler 1911, or Anaplasma ovis, Bevan 1912, babesiosis caused by Babesia bovis, Babes 1988 and Babesia bigemina, Smith & Kilborne 1893, and heartwater caused by Ehrlichia ruminantium Cowdry 1925. A cross-sectional survey was undertaken to determine the antibody prevalence of these TBDs and to identify the risk factors for TBD infections in the Union of the Comoros. In 2016 and 2017, 903 individual animal serum samples were collected from 429 separate farms, where the farmers answered individual questionnaires. The antibody prevalence of anaplasmosis, babesiosis (B. bigemina) and heartwater was determined by enzyme-linked immunosorbent assays (ELISA) and the antibody prevalence of ECF was assessed using an immunofluorescence antibody test (IFAT). The relationship between TBD seropositivity and livestock-related variables was assessed by multivariate analyses with standard logistic regression models. The results showed that these four TBDs were present in the Union of the Comoros with a global antibody prevalence of 15% (95% CI [12.7%; 17.3%]) for anaplasmosis, 9.2% (95% CI [6.5%, 11.9%]) for B. bigemina babesiosis, 5.3% (95% CI [3.2%, 7.4%]) for ECF and 4.6% (95% CI [3.2%, 6%]) for heartwater. We compared these findings with the abundance and distribution of several tick species known to be TBD vectors and we found a significant correlation between Rhipicephalus appendiculatus and ECF, and between Amblyomma variegatum and heartwater. We also found that two major variables were significantly correlated with B. bigemina antibody prevalence (“island” and