Clostridioides difficile is a major antibiotic-resistant, nosocomial bacterial pathogen that presents unique challenges across the age spectrum. While adults with C. difficile infection (CDI) can experience a range of symptoms from mild diarrhea to pseudomembranous colitis and death in severe cases, infants are clinically asymptomatic during colonization. Despite nearly a century of research on C. difficile, there are significant gaps in our understanding of infants’ unique relationship with C. difficile. Additionally, current preventative and therapeutic strategies for symptomatic CDI are insufficient, particularly for vulnerable populations. Herein, we describe two approaches to address these critical gaps. First, we demonstrate that neonatal mice offer a model system in which to systematically define the early-life impacts of colonization with C. difficile. For the first time, we show that early-life C. difficile, despite appearing asymptomatic, is not immunologically silent. Transcriptomics analysis of neonatal intestinal epithelial cells (IECs) coupled with functional organoid assays revealed that early-life C. difficile leads to pro-inflammatory and damage response repair mechanisms in the murine intestinal epithelium in a toxin-dependent manner. Interestingly, analysis of adult mice who had been colonized with C. difficile exclusively during early life revealed that the early-life effects of C. difficile are coupled with long-term reprogramming of the cellular composition of the intestinal epithelium and defects in the frequencies of innate lymphoid cells in the colonic lamina propria. Upon further investigation, we found that early-life C. difficile may increase susceptibility to enteric infections later in life, revealing long-term consequences of early-life carriage of C. difficile. In addition, we developed a novel messenger RNA-lipid nanoparticle (mRNA-LNP) vaccine targeting C. difficile toxins and non-toxin virulence factors, which we found to elicit robust and long-lived systemic and mucosal antigen-specific humoral and cellular immune responses across animal models and confer protection from lethal CDI in both primary and recurrent murine infection models. We also discovered that the inclusion of non-toxin cellular and spore antigens improved decolonization of toxigenic C. difficile from the gastrointestinal tract, addressing a critical gap in existing toxin-based immunotherapies. Moreover, we show here that maternal vaccination with an mRNA-LNP targeting C. difficile poses a promising passive immunization strategy for the prevention of toxin-induced effects of early-life C. difficile in neonates. This study provides new insights into the consequences of early-life C. difficile and establishes a promising vaccine platform to prevent CDI-associated disease. Taken together, we believe that the findings from this work have broad implications for understanding age-dependent host-pathogen interactions and advancing the development of next-generation CDI therapies.