Background: Infection with multidrug-resistant organisms (MDRO) in foot ulcers is a major cause of morbidity and mortality among diabetic patients in India. The empirical antibacterial therapy based on local prevalence and susceptibility pattern of bacterial isolates can significantly reduce the incidence of complications. Objectives: The study aimed to a) determine the microbiological profile and prevalence of MDRO isolated from diabetic foot infection; b) identify the main risk factors for MDRO; and c) find out the risk of a few selected complications in ulcers infected with MDRO. Materials and Methods: Specimens such as tissue/bone biopsy or syringe aspirates were collected for culture and antimicrobial sensitivity testing from patients with diabetic foot ulcers of Wagner grade ≥2. Cefoxitin disc diffusion method was used for the detection of methicillin-resistant Staphylococcus aureus (MRSA). Standard methods to detect ESBLs, AmpC β-lactamase, and metallo-beta-lactamase were used in multidrug-resistant Gram-negative isolates. Results: Out of 250 patients, 144 (58.3%) had polymicrobial infection and 172 (41.7%) of the 412 isolates were multidrug-resistant. Staphylococcus aureus was the single commonest organism, i.e., 139 (33.7%). Out of 139 Staphylococcus aureus isolates, 62 (44.6%) were MRSA. Gram-negative organisms accounted for the majority of isolates, i.e., 223 (54.1%). Out of 223 Gram-negative organisms, 108 (48.4%) were multidrug-resistant. The commonest Gram-negative bacterium was Pseudomonas aeruginosa, i.e., 77/223 (18.7%). Risk factors for MDRO and outcome of MDRO infection were also analysed. Conclusions: The prevalence of MDRO in our study was nearly 50%, which shows the urgent need for implementation of strict antibiotic policy and infection control measures to avoid antibiotic resistance. The presence of recurrent ulcer, past hospital stay, past foot-related surgery, ulcer size (>4 cm²) and ulcer duration >1 week were identified as the main risk factors for MDRO. Death during hospital stay was significantly higher in the MDRO group, while ulcer healing or amputation was not significantly associated. Finally, an empirical antibiotic policy was also proposed for treating diabetic foot infections.