Background: Eicosanoids are lipid signaling molecules involved in modulating the innate and adaptive immune response and therefore thought to be of importance in the host-defense against Mycobacterium tuberculosis (Mtb). Studies show that imbalance in the eicosanoid network is linked to altered Mtb susceptibility, although the role of eicosanoids in Tuberculosis (TB) remains poorly understood. The purpose of this systematic review is to illuminate the effects of eicosanoids in TB immunopathogenesis and investigate the internal relationship between eicosanoids and other components of the immunological response during Mtb infection. We also aim to elucidate the potential of targeting eicosanoids as adjunctive Host-directed therapy (HDT) to augment Mtb elimination/containment while minimizing tissue pathology. Method: We performed a systematic literature search in PubMed and Embase by using search terms that connected eicosanoids and tuberculosis. The search identified 562 articles, where our initial screen excluded 350 records. We included 130 studies based on full-text assessment. Results and conclusion: Our results show that eicosanoids have diverse and multifaceted effects in TB, where these effects include regulating bactericidal killing, as well as death modality of innate immune cells and production of other inflammatory mediators, which subsequently affects adaptive immune responses and granuloma formation. Further, we show that these effects are dependent on balance of eicosanoids, where opposing functions of pro- and anti-inflammatory eicosanoids modulates TB susceptibility. We present current reports targeting eicosanoids as adjunctive therapy in TB and the existing clinical trials listed using such therapy. Next, we present the challenges in using animal models as predictors of human TB-disease, as well as challenges in using experimental models, and discuss if such models are applicable to reflect the host response in humans during Mtb infection. Finally, we illuminate the challenges of using HDT targeting host eicosanoid biosynthesis, and the implications of using such treatment on the immunological response overall during Mtb infection.