Amblyomma variegatum, the tropical bont tick, is a species of veterinary importance being considered as one of major pest of ruminants in Africa and in the Caribbean, vector in particular of the rickettsiale Ehrlichia ruminantium, the etiological agent of heartwater. Tick’s saliva contains a complex mixture of bioactive molecules including proteins modulating host responses to ensure successful blood feeding, and as a side effect facilitating infection by pathogens. The general objective of this study was to determine the impact of E. ruminantium infection on the composition of A. variegatum sialome, in comparison with salivary glands and gut proteomes (entry and exit organs involved in nutrition and vectorization of pathogens). Salivation of semi-fed females was induced after detachment from feeding host by injection of pilocarpine, and ticks were further dissected for organs collection. Crude saliva proteins and proteins extracted were analysed using Orbitrap Q-Exactive mass spectrometer. Raw data analysis was performed using the MaxQuant software and homemade script “leading”. The data imputation methods tailored to the nature of missing values, enabled a precise protein profiling of each sialome and proteome, and provided valuable insights into their respective molecular profile. Among the proteins identified in A. variegatum saliva and organs, a bioinformatics functional analysis of molecular determinants highlighted immunomodulators that could, at least in part, explain the biological effects observed on host immune cells. Interestingly, E. ruminantium infection did not significantly modify the composition of tick saliva, suggesting a moderate cost to tick natural immunomodulatory capacities. Our results bring new insights for a better understanding of A. variegatum-E. ruminantium-ruminant hosts interactions at the molecular level.