Typhoid fever remains a major public health issue in Indonesia, with its true burden likely underreported due to diagnostic challenges. The clinical manifestations of typhoid fever are often nonspecific and overlap with other endemic febrile illnesses such as dengue, leptospirosis, and rickettsial infections, leading to frequent misdiagnosis. Although blood culture and PCR are the gold standards, their limited accessibility in Indonesia has resulted in reliance on suboptimal diagnostic tools such as the Widal test and TUBEX TF. Recent advances, including the Nelwan Score and CRP-based differentiation, have shown promise in improving early clinical screening. Furthermore, antibody-based proteomic diagnostics offer enhanced accuracy but remain largely confined to research settings. A combined approach utilizing validated clinical scores, affordable biomarkers, and selective use of serological tests is essential to improve diagnostic accuracy and patient care. Misdiagnosis not only endangers patient outcomes but also contributes to inappropriate antibiotic use, accelerating the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Salmonella Typhi. Resistance to first-line antibiotics and fluoroquinolones has been increasingly reported in Indonesia, although some regions still demonstrate preserved susceptibility. Cautious and evidence-based antibiotic prescribing is therefore critical to mitigating resistance. This article underscores the urgent need to strengthen diagnostic strategies and antimicrobial stewardship to address the persistent challenge of typhoid fever in Indonesia. © 2025, Indonesian Society of Internal Medicine. All rights reserved.