Background: In Ethiopia, Streptococcus pneumoniae is the predominant causative agent of pneumonia. About, 95% of bacterial pneumonia cases in under five years of children are caused by pneumococci. Objective: To assess the nasopharyngeal carriage of Streptococcus pneumoniae, its antibiotic susceptibility pattern, and associated factors among children in Southwest Ethiopia. Methods: A cross-sectional study was conducted from October 01, 2018, to December 30, 2018. A total of 293 children aged ≤15 years were included in the study using a systematic random sampling technique. A nasopharyngeal swab was collected using a sterile cotton swab and cultured on blood agar supplemented with 5μg/ml gentamicin. The antimicrobial susceptibility testing was performed using the Kirby-Bauer disc diffusion technique. Results: The ages of participants ranged from 5 months to 14 years. The carriage rate of Streptococcus pneumoniae was 74/293 (25.3%). Being within the age group <3 years, the habit of sleeping with parent(s)/guardians and numbers of rooms per household were significantly associated with pneumococcal carriage. Streptococcus pneumoniae showed the highest resistance to Tetracycline, 36 (48.65%), and Trimethoprim/sulfamethoxazole, 29 (39.2%), and was found to be susceptible to Chloramphenicol, 54 (77%), and Erythromycin, 38 (51.4%). Conclusion: The nasopharyngeal carriage rate of Streptococcus pneumoniae is considerably high. High antimicrobial resistance of Streptococcus pneumoniae against Tetracycline and Trimethoprim/sulfamethoxazole was observed. Living in a house with a single room, children’s habit of sleeping with parents/guardians and age are associated factors of high pneumococcal carriage. Strategies need to be designed to address the modifiable associated factors and the bacterium antibiotic resistance pattern should be monitored regularly.