The present study was conducted to prepare and evaluate the herbo-mineral emulgel formulation containing Curcuma longa, Datura metel, Aloe vera and and calcium hydroxide against bovine clinical mastitis. Extracts of selected plants were screened for phytochemicals. In Vitro antimicrobial screening of herbal extracts against isolated bacterial strains was performed by Agar disc-diffusion method. In Vitro antimicrobial activities of polyherbals (Curcuma longa, Datura metel and Aloe vera) and gentamicin sulphate (antibiotic agent) against Staphylococcus aureus, Streptococcus agalactiae and Escherichia coli isolates, alone and in combination were evaluated by minimum and fractional inhibitory concentrations study. Oil-in-water herbo-mineral emulsion was prepared using Cremophor EL and Tween 20. The optimized herbo-mineral emulsion was developed into emulgel using Carbopol 940 as a gelling agent and triethanolamine as alkalizer. Herbo-mineral emulgel formulations were evaluated for its pH, appearance, homogenecity, viscosity, spreadability, ex vivo permeation and stability. In vivo anti-inflammatory assay was done by carrageenan induced rat paw edema test. Acute dermal irritation study was conducted in rabbits. Clinical study was conducted in lactating cows to evaluate the efficacy herbo-mineral emulgel formulation against clinical mastitis. The phytochemicals screening showed the presence of alkaloids, flavonoids, glycosides, phenols, tannins, terpenoids, phlobatannins, saponins and carbohydrate compounds. Minimum and fractional inhibitory concentrations study showed that polyherbals in combination with gentamicin sulphate were able to provide stable synergistic therapeutic outcomes with higher efficacy in combating mastitis causing organisms in bovines. Based on In Vitro antimicrobial study, the extracts of Aloe vera, Datura metel, Curcuma longa and calcium hydroxide were taken in the ratio of 2:1:1:0.3 for the final formulation. The pH of emulgel (6.25± 0.30) was found to be in accordance with the range of udder skin pH. Herbo-mineral emulgel also illustrated efficient permeation (79.20 μL/cm2) through skin in 12 h. Viscosity (5720±85 cp), spreadability (10.02 ±0.12 g.cm/sec) indicated its suitability for topical application. Antimicrobial evaluation of polyherbal emulgel revealed broader zones of growth inhibitions against E.coli (16.35±0.58mm), S. aureus (19.23±1.05mm) and S. agalactiae (19.88±0.67mm). In vivo anti-inflammatory study showed that the anti-inflammatory effect of the herbo-mineral emulgel was significantly higher than the effect of Valdecoxib gel formulation and herbo-mineral formulation. Moreover, herbo-mineral emulgel was also found to be non-irritant. These parameters were consistent over 6 months. The Somatic cell counts and bacterial load in milk was significantly reduced in cows treated with herbo-mineral emulgel formulation. The results of clinical study indicated that the combined treatment i.e. herbo-mineral emulgel formulation topically along with systemic administration of gentamicin sulphate continuously for 5 days was most effective in the treatment of clinical mastitis as compared to herbo-mineral emulgel treatment alone or gentamicin sulphate treatment alone. From this study, it can also be concluded that the emulgel turned out to be a promising topical delivery of herbo-mineral containing Curcuma longa, Datura metel, Aloe vera and calcium hydroxide with enhanced therapeutic efficacy against clinical mastitis. Further, the herbo-mineral emulgel formulation will be an efficient and economically affordable formulation in the field to treat clinical mastitis immediately by farmers itself before getting help of veterinarians