No-reflow phenomenon (NRP) after primary PCI in STEMI is strongly linked to early mortality and adverse events. Conventional indices such as the systemic immune-inflammation index (SII), the CRP to albumin ratio (CAR), and the SYNTAX 1 score (SXscore) appear to provide only moderate discrimination for NRP. The endothelial activation and stress index (EASIX), calculated as LDH × creatinine / platelet count, reflects endothelial dysfunction and microvascular stress and may add to risk stratification. This two-center retrospective cohort study included 983 consecutive STEMI patients undergoing primary PCI. NRP was defined as the failure to achieve distal TIMI 3 flow despite a fully patent epicardial artery, or the need for pharmacological therapy to reverse NRP. We evaluated the relationships of EASIX, SII, CAR and SXscore with NRP; key exclusion criteria were non-ticagrelor P2Y12 loading, advanced renal/hepatic failure, active infection/inflammatory–hematologic disease or malignancy, shock/arrest (Killip ≥ 2), door-to-balloon time > 60 min, prior CABG/PCI, and pre-PCI fibrinolytic therapy. NRP occurred in 267 patients (27.2%). EASIX, SII, CAR and SXscore were significantly higher in the NRP (+) group (all p < 0.001). In multivariable models, EASIX (OR 18.97, 95% CI 11.83–30.43; p < 0.001), CAR (OR 2.45, 95% CI 1.90–3.16; p < 0.001), SII (OR 1.000, 95% CI 1.000–1.000; p = 0.003), and SXscore (OR 1.04, 95% CI 1.03–1.06; p < 0.001) were independently associated with NRP. In ROC analysis, EASIX demonstrated the highest discriminative ability for predicting NRP (AUC = 0.835). The optimal cut-off value of 1.248 provided 62.2% sensitivity and 93.6% specificity. In comparison, CAR, SII, and SXscore showed lower discrimination (AUC = 0.687, 0.562, and 0.583, respectively). EASIX demonstrated a stronger association with NRP than CAR, SII, and the SXscore. Easily derived from routine laboratory tests, EASIX may represent a practical and readily applicable index for early NRP risk stratification in STEMI.