Nitazoxanide (NTZ), an FDA-approved drug, served as the framework for synthesizing 22 new broad-spectrum antimicrobial agents from 4-aminosalicylic acid via protection–deprotection, Staudinger reduction, Clauson–Kaas pyrrole synthesis, and nucleophilic substitution. These compounds were evaluated for antibacterial, antimycobacterial, and antitrypanosomal activities. Several compounds, particularly 10, 11, 13, and 22, surpassed the antibacterial activity of NTZ and its active metabolite tizoxanide (TIZ) against all tested pathogens, with MICs ranging from 1.025 to 9.81 μM. Compounds 10 and 13 were twice as potent as ciprofloxacin against Klebsiella pneumoniae, while 11 and 17 were equipotent against Pseudomonas aeruginosa (MIC 5.34 μM). Compounds 11 and 14 matched ciprofloxacin against Staphylococcus aureus (MIC 3.20 and 2.98 µM), whereas 13 and 21 were 1.5- and 2.5-fold more potent against Enterococcus faecalis, respectively. Compound 10 outperformed ciprofloxacin against Helicobacter pylori (MIC 1.025 μM). Compounds 6 (MIC 9.46 μM) and 7 (MIC 16.78 μM) outperformed NTZ against Mycobacterium tuberculosis, and compound 3 emerged as a promising antitrypanosomal agent (MICs 2.59–4.73 μg/mL) against six Trypanosoma species. Cytotoxicity and pharmacokinetic studies confirmed the compounds’ favorable drug-like properties and high selectivity. Docking results showed strong binding to key targets like pyruvate ferredoxin oxidoreductase (PFOR), glucosamine-6-phosphate synthase (G6PS), dihydrofolate reductase (DHFR), and ornithine decarboxylase (ODC). Overall, several NTZ derivatives, particularly compounds 3, 6, 10, 11, 13, and 22, showed potent broad-spectrum antimicrobial activity and offer convenient leads for further optimization.