Background/Objectives: The prevention of sexual HIV-1 acquisition in women and girls in sub-Saharan Africa remains an important public health priority. Expanding the existing biomedical product portfolio to include long-acting vaginal products, such as intravaginal rings (IVRs), is expected to appeal to end users and drive adoption. Methods: We formulated two different triple-combination antiretroviral IVRs, both delivering the acid salt tenofovir (TFV), disoproxil fumarate (TDF), and the free base emtricitabine (FTC), with one delivering elvitegravir (EVG) as the free acid and the other as the sodium salt. The devices were evaluated for pharmacokinetics and local safety in two established preclinical models, sheep and pig-tailed macaques. Results: The IVRs were safe and maintained cervicovaginal fluid (CVF) drug concentrations that were above our efficacy targets derived from prior humanized mouse studies. All three agents were uniformly distributed vaginally, as evidenced by CVF and vaginal tissue measurements. Elevated drug concentrations were observed in macaque vaginal tissue samples collected three days after IVR removal, suggesting a possible forgiveness window. TFV and FTC concentrations in rectal tissue and fluid suggested potential for dual-compartment HIV-1 protection, although the vaginal-to-rectal drug transport mechanism appeared to differ across both species. The humanized mouse vaginal HIV-1 efficacy model was used to empirically compare combination effects when TDF, FTC, and EVG were co-administered, and TDF-EVG was identified as a promising combination to be developed further for IVR delivery in parallel with the triple combination.