The environmental risk factors of neuromyelitis optica spectrum disorder (NMOSD) are not fully specified. Regarding the evidence on the possible protective effects of whole grains and legumes against inflammatory disorders, we examined the association between the mentioned dietary components and NMOSD. 70 patients with NMOSD with definite diagnosis and 164 hospital-based controls were included in this case-control investigation. Data on demographic, clinical, and anthropometric characteristics were collected. Dietary habits of participants were assessed using a previously validated food frequency questionnaire (FFQ) containing 168 food items. Daily intakes of whole grains and legumes were calculated and classified in quartiles. The odds of suffering from NMOSD according to the quartiles of whole grains and legumes were measured in the form of logistic regression models. The mean amount of whole grains (115.29 vs. 44.14 g) and legumes (59.43 vs. 34.50 g) consumption was significantly higher in the control group versus the case group. There was a reverse association between whole grains or legumes and NMOSD odds in both models [P < 0.05, odds ratio (OR) < 1]. In the fully-adjusted model, 90% [95% confidence interval (CI): 0.02-0.39] and 92% (95% CI: 0.01-0.52) reduction in NMOSD odds was observed in the third and fourth quartiles of whole grains intake, respectively. Higher intake of legumes in the third and fourth quartiles led to 81% (95% CI: 0.05-0.71) and 95% (95% CI: 0.01-0.27) reduction in the odds of NMOSD, respectively. Aligned with the results of other investigations on inflammatory disorders, our results suggested a negative association between whole grains and legumes and NMOSD odds.