Microcystin-leucine-arginine (MC-LR) has been shown to induce neuroinflammation and disrupt neurotransmitter system. However, little is known about the mechanism of toxicity. In this study, male adult zebrafish (Danio rerio) were exposed to MC-LR at concentrations of 0, 0.1, 1, 10 μg/L for 30 days. Histomorphological evaluation revealed thrombus formation and vacuolization in the brains of zebrafish exposed to 10 μg/L MC-LR. Additionally, this exposure led to elevated MDA levels and decreased T-SOD, CAT and GSH levels in the brain, indicating oxidative stress. MC-LR exposure also significantly increased TNF-α and IL-1β contents and altered transcriptional levels of genes associated with the NOD/NFκB pathway (nod1, nod2, tak2, ripk2, ikbkb, nfkbiaa and nfkb2), implicating that MC-LR induced neuroinflammation. Concurrently, disruptions in neurotransmitter systems were observed, manifested by reductions in ACH, DA, 5-HT contents, an increase in Glu, and changes in related genes (ache, chran7a, dat, drd2b, 5htt, htr1aa, glsa and grin2aa). Partial least squares path modeling (PLS-PM) analysis showed that the oxidative stress and antioxidant defenses directly affected the cholinergic and glutamatergic systems and inflammatory response, as well as indirectly influenced the dopaminergic system via inflammation. Thus, our results suggested that oxidative stress may be a potential mechanism underlying the neuroinflammation and disruption of neurotransmitter systems induced by MC-LR. Furthermore, BMD modeling indicated that the BMDL values for ACH, T-SOD and MDA were all greater than 1 μg/L, suggesting that long-term exposure to MC-LR concentrations below 1 μg/L pose a relatively low risk of neurotoxicity. The lowest BMDL for MDA also implies that oxidative stress is a primary concern in the brain, making MDA a preferred biomarker for MC-LR exposure.