Objective: Secondary hemophagocytic lymphohistiocytosis (sHLH) is an increasingly recognized complication in patients with scrub typhus, potentially contributing to substantial mortality despite appropriate antibiotic treatment. This study aims to determine the prevalence and prognosis of sHLH and identify diagnostic factors in adult patients with scrub typhus in North India. Methods: This prospective cohort study was conducted at PGIMER, Chandigarh, from August 2021 to November 2023. sHLH was defined as an HScore of 200 or above. The diagnostic performance of biomarkers such as ferritin, fibrinogen, triglycerides, and C-reactive protein was assessed through receiver operating characteristic curve analysis, evaluating area under the curve (AUC), sensitivity, and specificity. Results: Out of 150 patients (mean age 39 years, 54% female), 28 (18.7%) were diagnosed with sHLH. Those presenting with high-grade fever, seizures, high pulse rate, hepatomegaly, splenomegaly, cytopenia, and significant hepatic dysfunction were more likely to have sHLH. Ferritin demonstrated the highest diagnostic utility (AUC 0.83), compared to fibrinogen (AUC 0.72), triglyceride (AUC 0.67), and C-reactive protein (AUC 0.69). The optimal cutoff for ferritin was 2000 ng/mL, with a sensitivity of 90% and a specificity of 66%. Higher ferritin thresholds (6000 ng/mL and 10000 ng/mL) increased specificity to 88% and 95%, respectively. Patients with sHLH often presented with multi-organ failure, necessitating mechanical ventilation and vasopressor support. In-hospital mortality was significantly higher in sHLH patients than in those without (21.4% vs 6.6%, p = 0.025). Conclusion: Early detection of sHLH using the HScore and ferritin significantly influences the management of scrub typhus, underscoring the necessity for tailored therapeutic strategies to improve patient outcomes.