Introduction. Chandraprabha Vati (CV) is an Indian polyherbal Siddha drug, traditionally used as an anti-inflammatory agent for arthritis and urinary ailments. This study explores its effect on mice with urinary tract infection. Materials and Methods. The in-organic constituents of CV were determined by atomic absorption spectroscopy and phytochemical analysis was carried out. The supplementing dose of CV to infected experimental mice was determined by in vitro antimicrobial assay. Transurethrally infected animals were supplemented with CV extract for 20 days after confirmation of UTI. The animals were euthanized as per the guidelines and the tissues were harvested from the control and infected mice for histopathological examination the antimicrobial peptide Tamm-Horsfall protein (THP) and inflammatory markers (tumor necrosis factor-α and nuclear factor kappa-light-chain-enhancer of activated B cells) to ascertain the modulatory effects of CV. Indicators for oxidative stress and protein levels were also quantified to validate the efficacy of CV. Results. Terpenoids and flavanoids were majorly found to constitute CV along with zinc and iron as in-organic content. Histological and immunohistochemical studies confirmed the pronounced infection in the kidney of the uropathogenic Escherichia coli-infected animals. Supplementation of CV significantly restored the increased levels of the antimicrobial proteins, THP, and inflammatory markers. Conclusions. This study explored the efficacy of the aqueous extract of CV as an alternative medication for the synthetic analogues administered for UTI. This study also provides information on the possible role of THP as an antimicrobial protein in the kidney in preventing infection due to uropathogenic E coli.