Background Invasive Staphylococcus aureus infection (ISA) is increasingly being recognized as an important cause of morbidity and mortality in developing countries. This problem is confounded by the increasing prevalence of antibiotic-resistant S. aureus. The aim of the study was to describe the clinical presentation and antibiotic susceptibility profile of ISA infection in a tertiary hospital in North West Nigeria. Materials and Methods This study was a prospective cohort study carried out on patients with ISA infection who were seen at a regional referral tertiary hospital in North West Nigeria. One hundred forty patients with ISA infection were studied. Clinical evaluation and relevant laboratory investigations were conducted. Antibiotic susceptibility tests were carried out by disk diffusion method according to Clinical and Laboratory Standard Institute guidelines. Results The mean age of the patients was 40.7 ± 15.6 years, with male-to-female ratio of 1.4:1. Skin and soft tissue infections (108 [77.1%]) and primary bacteremia (17 [12.1%]) were the most common diagnoses. Most infections were community-acquired infections (94 [67.1%]). Risk factors were identified in 112 (80%), of which diabetes mellitus (40 [35.7%]) and chronic kidney diseases (33 [29.5%]) predominate. Eighty-two (52.2%) of the isolates were methicillin-sensitive S. aureus, and 75 (47.8%) were methicillin-resistant S. aureus (MRSA). More cases of MRSA compared with methicillin-sensitive S. aureus were seen among patients with pneumonia and primary bacteremia. The overall mortality was 25 (19.7%) at 1-month follow-up. On multiple logistic regression analysis, the only factors predictive of mortality were sepsis (odds ratio, 6.723; 95% confidence interval, 1.431–31.585) and infection with MRSA (odds ratio, 5.523; 95% confidence interval, 1.506–20.250). Conclusions This study shows high burden of ISA with high prevalence of MRSA. This underscores the need for antimicrobial stewardship program and strengthening of infection control practices in our hospital.