Introduction: Submucosal laryngeal lesions may have significant diagnostic uncertainty as tumour mimics Although mycobacterium tuberculosis is the most common aetiology of laryngeal granulomas, non-tuberculous granulomas may arise from multiple aetiologies, including systemic autoimmune disease, intubation trauma, non-tuberculous infections, and malignancy. This paper presents a systematic review on infectious and autoimmune non-tuberculous laryngeal granuloma to elucidate a diagnostic pathway for this entity. Additionally, due to the heterogeneity of this condition, a case series of patients are examined to illustrate the diagnostic process. Methodology: Systematic review of MEDLINE, EMBASE, and Scopus from inception to 24th August 2024 of MeSH terms pertaining to “granuloma” and “larynx” was conducted according to PRISMA-P guidelines. (PROSPERO CRD42021238544) Case series data of the four patients from our institution was obtained from retrospective review of the electronic medical record. Results: Of 2621 unique studies identified, 331 studies underwent full-text screening, and nine papers with 44 patients met criteria for inclusion into the systematic review. Infectious causes of discrete non-tuberculous granuloma were leishmaniasis, histoplasmosis, laryngoscleroma, cryptococcosis, sporothrix schenckii, and botryomycosis. Autoimmune causes were amyloidosis. Multiple biopsies are common when the culprit organisms are not identified, and autoimmune testing is non-specific. Four patients in our case series presented with similar symptoms to those identified in the systematic review. Initial biopsies were non-diagnostic, and open biopsies were required to exclude malignancy prior to commencing treatment. Conclusion: Autoimmune and infectious mimics of laryngeal malignancy require a high index of suspicion to avoid aggressive surgical management. International collaboration may assist the creation of a diagnostic pathway for non-diagnostic laryngeal biopsies for granulomatous disease.