A new potent antiinfective and antiparasitic 2,3-dihydro-1H-indolizinium chloride, (1), was isolated from Prosopis glandulosa Torr. var. glandulosa. Three additional new (2–4) and one known (5), indolizidines were also isolated, and the dihydrochloride salts of 1–3 (compounds 6, 7 and 8) were prepared. Structures were determined by 1D and 2D NMR and mass spectra. Compound 1 showed potent in vitro antifungal activity against Cryptococcus neoformans and Aspergillus fumigatus (IC50 values = 0.4 and 3.0 μg/mL, respectively), and antibacterial activity against methicillin-resistant Staphylococcus aureus and Mycobacterium intracellulare (IC50 values of 0.35 and 0.9 μg/mL, respectively). The remarkable in vitro fungicidal activity of 1–4 against C. neoformans (MFCs = 0.63→1.25 μg/mL) and 2, 3, and 5 against A. fumigatus (MFCs = 0.63→2.5 μg/mL) were similar to amphotericin B, but >2–4-fold more potent than 6–8. Prosopilosidine (1) showed potent in vivo activity at 0.0625 mg/Kg/day/ip for 5 days in a murine model of cryptococcosis by eliminating ~76% of C. neoformans infection from brain tissue compared to ~83% with amphotericin B at 1.5 mg/Kg/day. Compounds 1 and 4 exhibited potent activity and high selectivity index (SI) values against chloroquine sensitive (D6) and chloroquine resistant (W2) strains of Plasmodium falciparum with IC50 values of 39 and 95 ng/mL, and 42 and 120 ng/mL, respectively; (chloroquine, IC50 = 17 and 140 ng/mL). Prosopilosine (1) also showed in vivo antimalarial activity with an ED50 value of ~2 mg/Kg/day/ip against Plasmodium berghei-infected mice after 3 days of treatment.