Background: Schistosomiasis affects more than 250 million people, and praziquantel remains the only drug available for treatment; however, its activity is restricted to adult worms. Previously, our group evaluated six thiazole derivatives (PBT1–PBT6) in vitro against adult Schistosoma mansoni, identifying PBT2, PBT5, and PBT6 as the most active compounds. The present study aimed to evaluate the in vitro activity of PBT2, PBT5, and PBT6 against schistosomula and juvenile worms, as well as their in vivo efficacy against adult S. mansoni. Methods: Mechanically transformed schistosomula and juvenile worms recovered from mice (21 days post-infection) were incubated with the compounds (12.5–200 μM). Cytotoxicity was assessed using murine splenocytes and peritoneal macrophages exposed to the same concentration range. For in vivo evaluation, infected mice were orally treated with compounds (50, 100, or 200 mg/kg) for five consecutive days. Results: All compounds induced 100% mortality in schistosomula and juvenile worms within 3 h of exposure at 100 and 200 μM. Parasite cell viability was markedly reduced (>90%) at concentrations between 50 and 200 μM. The LC₅₀ values ranged from 15.3 to 30.9 μM for schistosomula and from 27.8 to 34.9 μM for juvenile worms, with low cytotoxicity observed in mammalian cells (CC₅₀ ≥ 193.9 μM). In vivo treatment resulted in significant reductions in fecal egg counts (~80% at 200 mg/kg), total worm burden (~60%), and egg loads in liver and intestinal tissues, in addition to an increased proportion of dead eggs in the intestine. Conclusions: The evaluated thiazole derivatives demonstrated potent in vitro activity against immature stages of S. mansoni and significant in vivo efficacy against adult parasites, accompanied by favorable changes in key parasitological parameters. These findings reinforce the potential of thiazole-based compounds as promising multistage schistosomicidal candidates.