Background: Antibiotics are one of the commonly prescribed drugs over the world. Overprescribing of antibiotics may result in serious bacterial resistance. The main cause of inappropriate prescription of antibiotics is the absence of guidelines and protocols for its use. The aim of this study was to evaluate the appropriate use of ceftriaxone (broad-spectrum third generation cephalosporin antibiotic) in internal medicine wards of Wad Medani teaching hospital in Sudan, as well as comparing its use with reference to the standard of Sudan treatment guidelines and reliable references like British National Formula (BNF) and Sanford guide. Methods: Prospective cross –sectional study conducted in the internal medicine department at Wad Medani Teaching hospital by reviewing the files of all in-patients admitted to medical wards, who received ceftriaxone between November and December, 2018 and the appropriateness use of ceftriaxone was evaluated depending on six criteria: indication, dose, frequency, duration of treatment, culture and sensitivity test and drug –drug interaction Results: A total of 280 admitted patient’s treatment chart containing ceftriaxone injection were analyzed. Ceftriaxone was indicated empirically in 91.1% mostly for respiratory tract infection (35%). Ceftriaxone appropriate dose was given in 59% of patients, inappropriate frequency in 68.9% and incorrect duration in 51.1%. Co-administered drugs with major interaction in 3.6% of patients. Conclusions: This study revealed high inappropriate use of ceftriaxone where it was given without implementing culture and sensitivity test in the majority of patients. This may result in treatment failure so educational programs is recommended to address the irrational use of antibiotic.