Objectives: We sought to determine the prevalence of asymptomatic bacteriuria (ASB) in patients with sickle cell disease (SCD), the susceptibility profile of its agents and their extended-spectrum β-lactamase (ESBL) production. Methods: Fifty-nine patients with SCD and 116 healthy controls were investigated. Urine samples were collected and cultured by standard techniques. We used the disc diffusion technique to determine antibiotic susceptibility. ESBL was detected by the combination disc method and detection of blaSHV, blaTEM, and blaCTX-M genes by multiplex-polymerase chain reaction. Results: The prevalence of ASB was higher among patients with SCD (8.6%) than controls (0.9%) (p = 0.016), predominantly among females. Coagulase-negative staphylococci (n = 2; 33.3%) predominated among the isolates. Other uropathogens included Stenotrophomonas maltophilia, Acinetobacter baumannii, and Enterobacter cloacae. All isolates were sensitive to meropenem but were resistant to ceftazidime, ampicillin, and tetracycline. blaSHV, blaTEM, and blaCTX-M-15 were detected in Enterobacter cloacae. Conclusions: The prevalence of ASB is high in patients with SCD predominantly among females. Rare multidrug-resistant uropathogens were implicated. We posit a need for resistance surveillance programs and antibiotic stewardship to prevent treatment failure and reduce drug resistance.