Background The pathogenesis of diverticular disease (DD) is attributed to several aetiological factors (e.g. age, diet, connective tissue disorders) but also includes distinct intestinal motor abnormalities. Although the enteric nervous system (ENS) is the key-regulator of intestinal motility, data on neuropathological alterations are limited. The study aimed to investigate the ENS by a systematic morphometric analysis. Methods Full-thickness sigmoid specimens obtained from patients with symptomatic DD (n = 27) and controls (n = 27) were processed for conventional histology and immunohistochemistry using anti-HuC/D as pan-neuronal marker. Enteric ganglia, nerve and glial cells were quantified separately in the myenteric, external and internal submucosal plexus compartments. Key Results Compared to controls, patients with DD showed significantly (P < 0.05) (i) reduced neuronal density in all enteric nerve plexus, (ii) decrease of ganglionic nerve cell content in the myenteric plexus, (iii) decreased ganglionic density in the internal submucosal plexus, (iv) reduced glial cell density in the myenteric plexus, (v) decrease of ganglionic glial cell content in the myenteric plexus and increase in submucosal plexus compartments, (vi) increased glia index in all enteric nerve plexus. About 44.4% of patients with DD exhibited myenteric ganglia displaying enteric gliosis. Conclusions & Inferences Patients with DD show substantial structural alterations of the ENS mainly characterized by myenteric and submucosal oligo-neuronal hypoganglionosis which may account for intestinal motor abnormalities reported in DD. The morphometric data give evidence that DD is associated with structural alterations of the ENS which may complement established pathogenetic concepts.