Background/Objectives: Direct-acting antivirals vary by lineage and face rapid resistance. We identified the oxazole-4-carboxamide lead KB-2777 and aimed to define its in vitro activity across α/β-coronaviruses, time-of-addition (TOA) profile, host-response signatures, and combinability with benchmark DAAs. Methods: We tested KB-2777 (≤25 μM) against HCoV-NL63 (LLC-MK2), HCoV-OC43 (Vero E6; MRC-5 for transcript profiling), and PEDV (Vero E6). We quantified extracellular viral RNA by RT-qPCR at 72 h (n = 3) and confirmed activity by spike-protein immunofluorescence (IFA), cytopathic effect (CPE) protection, and TCID₅₀. We compared TOA regimens (full, pre, co, post), evaluated combinations with nirmatrelvir (NL63) or GS-441524 (OC43) using ZIP scores, and profiled infection-context transcripts (IL6, IFNB1, ISG15, NRF2/antioxidant, UPR). Results: KB-2777 reduced viral RNA with EC₅₀ 5.27 μM (NL63), 1.83 μM (OC43), and 1.59 μM (PEDV) without cytotoxicity in the tested range. In NL63 post-treatment, inhibition was minimal at 24 h but clear at 48–72 h (EC₅₀ 2.42 μM at 48 h; 5.25 μM at 72 h). TCID₅₀ decreased at 48 h (12.5–25 μM, n = 3, p < 0.0001), and IFA/CPE corroborated antiviral activity. TOA ranked full > pre ≈ post > co. Combinations were additive to synergistic (ZIP 5.16 with nirmatrelvir; 8.40 with GS-441524). In OC43-infected MRC-5 cells, KB-2777 attenuated IL6, IFNB1, ISG15, and selected UPR transcripts, with limited changes in uninfected cells (n = 3). Conclusions: KB-2777 shows reproducible cell-based anti-coronavirus activity across α/β lineages, a TOA signature consistent with early post-entry host modulation, and favorable, non-antagonistic combinability with DAAs. These findings support target deconvolution, SAR/ADME optimization, and evaluation in primary airway and in vivo models.