Nosocomial infections, particularly in intensive care units (ICUs), present significant challenges due to invasive procedures and prolonged hospital stays. These infections lead to increased morbidity, mortality, and healthcare costs. Objectives: This study aims to determine the prevalence, identify common pathogens, analyze antibiotic resistance patterns, and evaluate risk factors associated with nosocomial infections in the ICU of a tertiary care hospital in Central India. Methods: A prospective observational study was conducted over 18 months (May 2022 to October 2023) in a 32-bed ICU. Data from 679 ICU admissions were analyzed, excluding patients with pre-existing infections. Pathogen identification and antibiotic susceptibility testing were performed according to Clinical Laboratory Standards Institute (CLSI) guidelines. Infection rates were calculated using CDC criteria. Results: Among the 679 patients, 166 (24.44%) developed device-associated infections, including 73 cases of catheter-associated urinary tract infections (CAUTI) (10.75%), 86 cases of central-line-associated bloodstream infections (CLABSI) (13.50%), and 39 cases of ventilator-associated pneumonia (VAP) (6.15%). Predominant pathogens included Pseudomonas aeruginosa, Acinetobacter species, and Klebsiella pneumoniae, with high resistance to cefotaxime, ceftazidime, and ciprofloxacin. Significant risk factors were diabetes, chronic obstructive pulmonary disease (COPD), and prolonged ICU stays. Mortality was higher in patients with device-associated infections (48.7%) compared to those without (31.5%). Conclusion: Nosocomial infections in the ICU are prevalent and associated with high mortality. The dominant pathogens and their resistance patterns highlight the need for stringent infection control practices and robust antimicrobial stewardship programs. Targeted interventions addressing identified risk factors can reduce infection rates and improve patient outcomes in critical care settings.