Background: High-density lipoprotein cholesterol (HDL-C) is traditionally considered protective in cardiovascular disease, but its role in acute ischemic stroke (AIS) remains unclear, particularly in patients undergoing mechanical thrombectomy (MT). This study aimed to assess the association between HDL-C levels and clinical outcomes in AIS patients treated with MT for anterior circulation large vessel occlusion (LVO). Methods: We conducted a multicentre, observational, post hoc analysis of AIS patients treated with MT between January 2016 and March 2023 across three stroke centers. HDL-C levels at admission were categorized, and outcomes included 90-day functional dependence (mRS: 3–6), symptomatic intracranial hemorrhage (sICH), hemorrhagic transformation, and 90-day mortality. We used logistic regression with restricted cubic splines to define an HDL-C threshold associated with increased risk and applied inverse probability weighting (IPW) to adjust for confounding. Results: Among 2166 patients (median age: 71 years; 52.3% female), HDL-C levels > 1.33 mmol/L were independently associated with a higher risk of poor functional outcome at 90 days (risk ratio (RR): 1.72, 95% confidence interval (CI): 1.55–1.90), increased odds of sICH (RR: 2.3, 95% CI: 1.64–3.12), and higher mRS shift (OR: 2.10, 95% CI: 1.79–2.46). Subgroup analyses revealed significant sex-specific differences, with women at greater risk of adverse outcomes at higher HDL-C levels. Conclusion: Elevated HDL-C levels (>1.33 mmol/L) are associated with worse functional outcomes and increased hemorrhagic complications following MT for anterior circulation AIS.