Abstract: Natural selection acts on all organisms, including parasites, to maximize reproductive fitness. Drug resistance traits are often associated with life‐history costs in the absence of treatment. Schistosomiasis control programmes rely on mass drug administration to reduce human morbidity and mortality. Although hotspots of reduced drug efficacy have been reported, resistance is not widespread. Using Bayesian state‐space models (SSMs) fitted to data from an in vivo laboratory system, we tested the hypothesis that the spread of resistant Schistosoma mansoni may be limited by life‐history costs not present in susceptible counterparts. S. mansoni parasites from a praziquantel‐susceptible (S), a praziquantel‐resistant (R) or a mixed line of originally resistant and susceptible parasites (RS) were exposed to a range of praziquantel doses. Parasite numbers at each life stage were quantified in their molluscan intermediate and murine definitive hosts across four generations, and SSMs were used to estimate key life‐history parameters for each experimental group over time. Model outputs illustrated that parasite adult survival and fecundity in the murine host decreased across all lines, including R, with increasing drug pressure. Trade‐offs between adult survival and fecundity were observed in all untreated lines, and these remained strong in S with praziquantel pressure. In contrast, trade‐offs between adult survival and fecundity were lost under praziquantel pressure in R. As expected, parasite life‐history traits within the molluscan host were complex, but trade‐offs were demonstrated between parasite establishment and cercarial output. The observed trade‐offs between generations within hosts, which were modified by praziquantel treatment in the R line, could limit the spread of R parasites under praziquantel pressure. Whilst such complex life‐history costs may be difficult to detect using standard empirical methods, we demonstrate that SSMs provide robust estimates of life‐history parameters, aiding our understanding of costs and trade‐offs of resistant parasites within this system and beyond. [ABSTRACT FROM AUTHOR]