The Northern part of Ghana lies within the African meningitis belt and has historically been experiencing seasonal meningitis outbreaks. Despite the continuous meningitis outbreak in the region, the risk factors contributing to the occurrence of these outbreaks have not been clearly identified. This study, therefore, sought to describe the clinical characteristics and possible risk factors associated with meningitis outbreaks in the Upper West Region (UWR). A 1:2 matched case-control study was conducted in May-December 2021 to retrospectively investigate possible risk factors for meningitis outbreak in the UWR of Ghana between January and December 2020. Cases were persons with laboratory confirmed meningitis, and controls were persons of similar age and sex without meningitis living in the same house or neighborhood with a confirmed case. Both primary and secondary data including clinical, socio-demographic and laboratory information were collected and entered on standard questionnaires. Data was analyzed using descriptive statistics and conditional logistic regression. Meningitis cases were mostly due to Streptococcus pneumoniae (67/98; 68.37%), followed by Neisseria meningitides serogroup X (27/98; 27.55%). Fever occurred in 94.03% (63/67) of Streptococcus pneumoniae cases and 100% in both Neisseria meningitidis serogroup X (27/27) and Neisseria meningitidis serogroup W groups (3/3). CSF white cell count was significantly associated with the causative agents of meningitis. Conditional logistic regression analysis showed that, passive exposure to tobacco [AOR = 3.65, 95%CI = 1.03-12.96], bedrooms with 3 or more people [AOR = 4.70, 95%CI = 1.48-14.89] and persons with sore throat infection [AOR = 8.97, 95%CI = 2.73-29.43] were independent risk factors for meningitis infection. Headache, fever and neck pain continue to be the most common symptoms reported by meningitis patients. Education and other preventive interventions targeting exposure to tobacco smoke and crowded rooms would be helpful in reducing meningitis outbreaks in the Upper West Region of Ghana.