Tuberculosis remains a serious health problem responsible to cause millions of deaths annually. The scenario becomes alarming when it is evaluated that the number of new drugs does not increase proportionally to the emergence of resistance to the current therapy. Furoxan derivatives, known as nitric oxide donors, have been described to exhibit a wide range of biological activities, including antitubercular. Herein, a novel series of twelve hybrid furoxanyl (1,2,5-oxadiazole 2-N-oxide) derivatives was designed, synthesized and evaluated in vitro against Mycobacterium tuberculosis H37Rv using the Resazurin Microtiter Assay (REMA) method. The furoxan derivatives have exhibited MIC₉₀ values ranging from 1.03 to 62 µM. For most active compounds, the selectivity index ranged from 3.78 – 52.74 (MRC-5) and 1.25 – 34.78 (J774A.1). Furthermore, these most active compounds were also evaluated against a clinically isolated multi-drug resistant strain (isoniazid, rifampicin, streptomycin and etambutol) and exhibited MIC₉₀ values ranging from 1.44 to 5.63 µM. The MIC₉₀ values of the four selected compounds were greater than several first and second line antitubercular drugs, such as ethambutol (2.4 µM), pyrazinamide (>48 µM), cycloserine (245 µM) and kanamycin (3.4 µM). In addition for those compounds, values of logP_o/w vary between 2.1 – 2.9, reaching the optimal range for oral administration. The amount of nitric oxide (NO) released was indirectly detected by Griess reaction through the measurement of nitrites in the medium. All compounds were able to release NO at levels ranging from 0.16 – 44.23%. Among the series, the phenylsulfonylfuroxan derivatives were the best NO-donor with the lowest MIC₉₀ values. The most active compound was also stable at different pHs in a chemical stability study (5.0 and 7.4). In conclusion, furoxan derivatives were identified as new promising compounds useful to treat sensitive and resistant tuberculosis. Currently, metabolomics and transcriptome analysis are underway in order to elucidate the possible mechanism of action of these compounds as well as an antitubercular activity study in vivo for the most potent furoxan derivative.