Purpose: The objective of this study was (1) to systematically review the evidence of routine post-nasal space blind biopsies and/or imaging of adults with isolated serous otitis media (SOM) of unknown cause for detection nasopharyngeal malignancy (NPM), and (2) to design a clinical management algorithm for these patients. Methods: A systematic search was conducted in the databases PubMed, Embase and Cochrane Library guided by the study question “Should adults with isolated SOM of unknown cause undergo routine biopsies of the post-nasal space and/or diagnostic imaging for detection of NPM?”. All retrieved studies were reviewed and quantitatively analyzed. Results: The systematic literature search identified 552 publications accessible for title-abstract screening. This yielded 23 studies for full text assessment, of which 6 were found eligible for inclusion. All six studies dealt with nasopharyngeal blind biopsies, whereas no studies on cross-sectional imaging were identified. The derived summarized results of the included studies showed that 5.5% (31/568) of patients with isolated SOM of unknown cause were diagnosed with NPM. Of these, 6.5% (2/31) had normal nasopharyngeal endoscopy (i.e., malignancy was discovered by blind biopsies). Finally, 0.35% (2/568) of patients with isolated SOM of unknown cause diagnosed with NPM had normal nasopharyngeal endoscopy findings (i.e., nasopharyngeal endoscopy ruled-out malignancy in 99.65% of patients). Conclusions: We found no evidence supporting routine use of blind biopsies or cross-sectional imaging in adults with isolated serous otitis media of unknown cause. We propose a pragmatic management algorithm for workup of adults with persistent secretory otitis media.