Postweaning diarrhea (PWD) is a significant concern in the swine industry, causing substantial economic losses due to decreased growth rates, increased mortality, and the extensive use of antimicrobials. Certain Escherichia coli (E. coli) pathovars are frequently implicated in PWD cases among piglets. Regular surveillance and testing of E. coli susceptibility to different antimicrobials is essential. This helps veterinarians and farmers select appropriate treatments, avoid unnecessary antibiotic use, and prevent the further spread of antimicrobial resistance (AMR). Herein, we tested the susceptibility to fourteen antimicrobials of 251 E. coli strains isolated from fecal samples of diarrheic (n = 148) and apparently healthy piglets (n = 103) in farms in Catalonia. The results of this study showed that 41.4% of the E. coli were multidrug-resistant (MDR) strains, presenting high resistance to conventional veterinary antimicrobials such as erythromycin, amoxicillin, streptomycin, tetracycline, lincospectin, sulfamethoxazole/trimethoprim, and florfenicol. A special concern was also observed for human last-resort antimicrobials, like quinolones and colistin. Moreover, pigs suffering from diarrhea had a higher frequency of infection with MDR strains than the healthy ones. To reduce the incidence and impact of PWD in pig herds, optimization of antimicrobial therapies had to be implemented with other strategies, such as good hygiene practices, optimizing nutrition, managing stress levels, and employing proper vaccination protocols.