Introduction: Early initiation of end-of-life (EOL) care in terminally ill patients can reduce the administration of unnecessary medications, minimize laboratory and radiological investigations, and avoid procedures that can provoke untoward complications without substantial benefits. This retrospective observational study was performed to compare early vs late initiation of EOL care in terminally ill ICU patients after the recognition of treatment futility. Materials and methods: The medical records of all patients who were considered to be terminally ill any time after ICU admission between January 2014 and December 2018 were extracted from the ICU database. The patients who were recognized for treatment futility were eligible for inclusion. The patients who were already on EOL care prior to the ICU admission or whose diagnosis was unconfirmed were excluded from the study. The treatment futility was a subjective decision jointly undertaken by the primary physician and the intensivist based upon the disease stage and the available therapeutic options. The commencement of EOL care after recognition of treatment futility was divided into (a) early group (EG)—within 48 hours of decision of treatment futility and (b) late group (LG)—after 48 hours of recognition of treatment futility. Both the groups were compared for (a) ICU mortality, (b) length of ICU stay, (c) number of antibiotic-free days, (d) number of ventilator-free days, (e) number of medical and/or surgical interventions (insertion of central lines, drains, IABP, etc.), (f) number of blood and radiological investigations, and (g) satisfaction level of family members. Results: Out of 107 terminally ill patients with diagnosis of treatment futility, 64 patients (59.8%) underwent early initiation of EOL against delayed initiation in 43 (40.2%) patients (1.3 ± 0.4 days vs 5.1 ± 1.6 days; p = 0.01). The patients in the late initiation group were younger in age (49 ± 3.6 years vs 66 ± 5.3 years; p = 0.03). The number of antibiotic-free days was higher in the early initiation group (12 ± 5.2 days vs 6 ± 7.5; p = 0.02). The number of medical and surgical interventions was lesser in the early initiation group (3.0 ± 0.7 episodes vs 12 ± 3.9 episodes; p = 0.007). The late initiation of EOL was caused by prognostic dilemma (30.2%), reluctance of the family members (44.1%), ambivalence of the primary physician (18.6%), and hesitancy of the intensivist (6.9%). The satisfaction level of the family members was similar in both the groups. Conclusion: We conclude that delayed initiation of EOL care in terminally ill ICU patients after recognition of treatment futility can increase the antibiotic usage and medical and/or surgical interventions with no effect on the satisfaction level of the family members.