Objectives: The study determined the prevalence of malaria infection and its association with socio-demographics, environmental, housing, and co-morbid ailment factors. Methods: The study was a cross-sectional of 330 consented adult febrile patients who were recruited at a tertiary health facility in rural Southwestern Nigeria. The standardized interviewer-administered questionnaire sought information on their socio-demographics, environmental, housing, and co-morbid ailment factors. Venous blood samples were collected and processed for malaria parasite detection, retroviral screening, glycated hemoglobin, and hemoglobinopathy. Data were analyzed using SPSS version 20. The strength of the association between independent and dependent variables was measured using odds ratio and 95% confidence interval with a significant level ( p value <0.05). Results: The prevalence of malaria parasitemia was 63.3% (95% confidence interval: 57.9%–68.5%). Being a farmer ( p = 0.002), lack of formal education ( p = 0.043), low-income earners ( p = 0.031), presence of bushes ( p = 0.048), stagnant water ( p = 0.042), not sleeping under long-lasting insecticide-treated nets ( p < 0.001), and sickle cell disease ( p = 0.041) were significantly associated with malaria infection. Conclusion: The study revealed that there is a high prevalence of malaria infection in rural Southwestern Nigeria. There may be a need to pay greater attention to adult populations in rural areas for malaria intervention and control programs.