Diffusion MR images are prone to severe geometric distortions induced by head movement, eddy-current and inhomogeneity of magnetic susceptibility. Various correction methods have been proposed that depend on the choice of the acquisition settings and potentially provide highly different data quality. However, the impact of this choice has not been evaluated in terms of the ratio between scan time and preprocessed data quality. This study aims at investigating the impact of six well-known preprocessing methods, each associated to specific acquisition settings, on the outcome of diffusion analyses. For this purpose, we developed a comprehensive toolbox called Diffuse which automatically guides the user to the best preprocessing pipeline according to the input data. Using MR images of 20 subjects from the HCP dataset, we compared the six pre-processing pipelines regarding the following criteria: the ability to recover brain’s true geometry, the tensor model estimation and derived indices in the white matter, and finally the spatial dispersion of six well known connectivity pathways. As expected the pipeline associated to the longer acquisition fully repeated with reversed phase-encoding (RPE) yielded the higher data quality and was used as a reference to evaluate the other pipelines. In this way, we highlighted several significant aspects of other pre-processing pipelines. Our results first established that eddy-current correction improves the tensor-fitting performance with a localized impact especially in the corpus callosum. Concerning susceptibility distortions, we showed that the use of a field map is not sufficient and involves additional smoothing, yielding to an artificial decrease of tensor-fitting error. Of most importance, our findings demonstrate that, for an equivalent scan time, the acquisition of a b0 volume with RPE ensures a better brain’s geometry reconstruction and local improvement of tensor quality, without any smoothing of the image. This was found to be the best scan time/data quality compromise. To conclude, this study highlights and attempts to quantify the strong dependence of diffusion metrics on acquisition settings and preprocessing methods.