Background Differentiating the non-sinogenic headache from chronic rhinosinusitis (CRS) remains a significant clinical challenge due to the extensive overlap in symptoms. The objective of this study was to evaluate the 22-item Sino-Nasal Outcome Test (SNOT-22) score patterns in patients with confirmed non-sinogenic headache in order to develop negative predictors of CRS. Methods Institutional Review Board (IRB)-approved, retrospective review of patients diagnosed with CRS or non-sinogenic headache defined as patients with a chief complaint of headache, facial pain, and facial pressure in the absence of both endoscopic and computed tomography (CT) evidence of inflammation. The optimal cutoff points of potential predictors of non-sinogenic headache by SNOT-22 score were quantified by receiver operating characteristic (ROC) curve. The negative predictive values (NPVs) for CRS were calculated in a discovery population and then validated in an independent population. Results A total of 724 (164 non-sinogenic headache and 560 CRS) and 412 (88 non-sinogenic headache and 324 CRS) patients were recruited in the discovery and validation populations, respectively. Domain 3 (Ear/facial) and domain 4 (Psychological dysfunction) were significantly higher in patients with non-sinogenic headache as compared with CRS while domain 1 (Rhinologic) and domain 2 (Extranasal rhinologic) were significantly lower. The top 4 predictors of non-sinogenic headache were the domain 3 (Ear/facial)/domain 1 (Rhinologic) ratio, item 12, domain 3 (Ear/facial), and (item 12 + item 10)/(item 4 + item 5) ratio, with areas under the ROC curve (AUCs) ranging from 0.637 to 0.720 by ROC curve. A domain 3 (Ear/facial)/domain 1 (Rhinologic) ratio over 0.66 performed as the best negative predictor of CRS with the highest NPVs of 0.880 and 0.889 in the discovery and validation populations, respectively. Conclusion Patients with non-sinogenic headache have distinct SNOT-22 score patterns compared with patients with CRS. A domain 3 (Ear/facial)/domain 1 (Rhinologic) ratio greater than 0.66 is a strong negative predictor of CRS, which can be used to aid in patient counseling and potentially limit the use of unnecessary sinonasal therapeutics.