Semi-intensive dairy systems are prevailing in tropical and subtropical countries that need to be probed for public health concern pathogens. The current study was designed to map trends in prevalence of dairy-originated E. coli, associated risk factors, and altering in-vitro drug susceptibility patterns. A total of n=200 subclinical mastitis milk samples were intended to be collected using purposive sampling method from semi-intensive dairy systems for which n=764 dairy animals (n=440 buffaloes, n=324 cattle) were screened. Standard biochemical and microbiological methods coupled with polymerase chain reaction (23sRNA) were applied to identify E. coli from subclinical milk samples. The study, overall, found a 26.18% (200/764) prevalence of subclinical mastitis and 13.50% (27/200) E. coli from subclinical samples. Among assumed risk factors, lack of use of teat dip (OR=8.26, C.I. = 2.73–24.91), higher age groups (OR=17.87, C.I. = 4.42–72.16), parity number >3 (OR=3.68, C.I. = 1.59–8.49), underweight animals (OR=2.89, C.I. = 1.11–7.53), and mid-lactation (OR=14.94, C.I. = 3.04–73.24) were dominant potential risk factors for E. coli infection. Antibiogram showed 42.86 and 21.43% of E. coli isolates resistant to amoxicillin-clavulanate and oxytetracycline, respectively. It was noted that more than 40% (42.86, 60.87, 57.89, 66.86, and 67.86%) of E. coli fall in intermediate susceptible cadre against 62.5% of tested antibiotics. In conclusion, increasing percentages of E. coli, higher number of potential risk factors, and antibiotic susceptibility inclining towards resistance demands stern compliance in anticipated time to avoid any grave situation.