Rodents play a significant role in the transmission of zoonotic diseases; anthropization has increased human contact with these animals, vectors of infectious agents. However, the processes driving parasitism of hosts remains poorly understood. Yersinia pestis, Rickettsia spp., and Francisella tularensis are three infectious agents transmitted to humans through ectoparasites, with rodents serving as the primary reservoirs. To explore the relationship between both intrinsic and extrinsic factors on host pathogen status, we evaluated heteromyid rodents in the Chihuahuan desert (ChD). From December 2022 to May 2023, we sampled 213 rodents at three locations with different anthropization levels. A total of 103 rodent blood samples, 84 organ samples, and 204 collected ectoparasites were analyzed for molecular detection of infectious agents (Y. pestis, Rickettsia spp., and F. tularensis) with PCR. We captured seven species of rodents (Dipodomys ordii, D. merriami, D. spectabilis, Chaetodipus hispidus, Ch. eremicus, Perognathus flavus, and P. flavescens) and identified one tick (Rhipicephalus sanguineus), two fleas (Meringis altipecten and M. dipodomys) and one louse (Fahrenholzia spp.). Molecular analyses yielded positive for Y. pestis, Rickettsia spp., and negative for F. tularensis. We then modelled the pathogen status as a function of intrinsic (body condition and sex) and extrinsic factors (locality, anthropization level, season, sample type, and parasite-infestation status). We found that non-parasite-infested individuals with better body condition have a higher probability of pathogen infection. Furthermore, we observed that blood samples had a higher probability of detecting pathogen-infected individuals, as compared to spleen or liver samples. Our results offer important insights into host–pathogen interactions and the role of body condition in the pathogen status.