In addition to histopathological parameters, evaluation of associated hematological factors is essential for devising a sensitive prognostic scale in glioma. Increased neutrophil-lymphocyte ratio (NLR), a marker of systemic inflammatory response, has recently been associated with worse outcome in various cancers. Given that glioma progression is characterized by inflammation, aggressive angiogenesis, and invasion, increased levels of systemic human-chitinase-3-like-one protein (YKL-40) have also been linked to poor prognosis. The aim of the present study was to assess the plausible association of YKL-40, NLR, and platelet count with increasing tumor grade, and evaluate their status as independent prognostic factors in terms of overall survival (OS) in therapy naive patients with diffuse glioma. Plasma levels of both biochemical markers in 72 diffuse gliomas, median age 42 years, were compared with 36 controls. Comparison of YKL-40, NLR, and PC with respect to tumor grade was found to be significant for each of the markers (P < 0.0001) while an inverse significant correlation was seen for YKL-40 and NLR with OS (r = -0.4619, P < 0.0001, and r = -0.5561, P < 0.0001, respectively). NLR was the best performing marker with AUC 0.9417 at 97% specificity. In addition, YKL-40 had a positive correlation with NLR (r = 0.4902, P < 0.0001), indicating that expression of both markers was linked to inflammation and tumor progression as they were significantly correlated with tumor grade. Expression of YKL-40 and NLR was independently associated with worse survival (HR 1.0062, P = 0.039, and HR 1.1787, P = 0.0003, respectively), thus establishing their clinical utility as prognosticators for diffuse gliomas.