The inactivation of bacterial endospores continues to be the main curtailment for further adoption of high-pressure processing in intrastate, interstate, and global food commerce. The current study investigated the effects of elevated hydrostatic pressure for the inactivation of endospore suspension of three indicator spore-forming bacteria of concern to the food industry. Additionally, the effects of four bacteriocin/bactericidal compounds were studied for augmenting the decontamination efficacy of the treatment. Elevated hydrostatic pressure at 650 MPa and at 50 °C was applied for 0 min (untreated control) and for 3, 7, and 11 min with and without 50K IU of nisin, 224 mg/L lysozyme, 1% lactic acid, and 1% CitricidalTM. The results were statistically analyzed using Tukey- and Dunnett’s-adjusted ANOVA. Under the condition of our experiments, we observed that a well-designed pressure treatment synergized with mild heat and bacteriocin/bactericidal compounds could reduce up to >4 logs CFU/mL (i.e., >99.99%) of bacterial endospores. Additions of nisin and lysozyme were able, to a great extent, to augment (p < 0.05) the decontamination efficacy of pressure-based treatments against Bacillus amyloliquefaciens and Bacillus atrophaeus, while exhibiting no added benefit (p ≥ 0.05) for reducing endospores of Geobacillus stearothermophilus. The addition of lactic acid, however, was efficacious for augmenting the pressure-based reduction of bacterial endospores of the three microorganisms.