Background <p>MicroRNAs (miRNAs) are key regulators and potential biomarkers for early diagnosis and prognosis of sepsis. To investigate the diagnostic and prognostic value, and molecular mechanism of miR-1290 in sepsis.</p> Methods <p>Enrollment comprised 127 healthy controls and 133 patients with sepsis. RT‑qPCR measured serum miR-1290 and TAO Kinase 1 (TAOK1) levels. ROC curve and Logistic regression assessed diagnostic efficacy and risk prediction of miR-1290 for sepsis. Kaplan-Meier and Cox regression evaluated its short-term prognostic value. An LPS-induced macrophage (THP-1) inflammation model was established to examine the effects of miR-1290 on cell viability (CCK-8), inflammatory cytokines TNF-α, IL-6, and IL-1β (ELISA), and macrophage polarization markers (RT-qPCR). Bioinformatic prediction and dual-luciferase reporter verified the interaction between miR-1290 and TAOK1, and rescue experiments were conducted to determine that TAOK1 reverses the biological functions of miR-1290.</p> Results <p>miR-1290 was downregulated in patients with sepsis and showed high diagnostic value. Its expression level was negatively correlated with both SOFA and APACHE II scores, and demonstrated good predictive performance for short-term mortality. In the LPS-induced macrophage model, overexpression of miR-1290 suppressed TAOK1 expression, elevated cell viability, suppressed the secretion of TNF-α, IL-6, and IL-1β, inhibited M1 polarization (downregulation of iNOS and CD86), and enhanced M2 polarization (upregulation of CD206 and Arg-1). Moreover, TAOK1 overexpression reversed the anti-inflammatory and protective effects of miR-1290.</p> Conclusions <p>Downregulated miR-1290 shows potential as both a diagnostic and prognostic indicator in sepsis. It may exert a protective effect on macrophages by targeting TAOK1, thereby inhibiting disease progression.</p>