The SARS-Cov-2, the causative organism of COVID-19 pandemic, is a highly transmissible, enveloped, single stranded, RNA virus that has mutated into several variants, complicating vaccine strategies and drug resistance. Novel treatment modalities targeting conserved structural vulnerable points are essential to combat these challenges. A true experimental pretest and post-test study design was applied in order to assess the effect of high frequency ultrasound on SARS-Cov-2 viral load under controlled laboratory biosafety setup. Since detailed imaging tools are unavailable for analysis, viral disruption was indirectly measured with the real time PCR cycle threshold (Ct) values. Ct values increased significantly after high-frequency ultrasound exposure, indicating a reduction in detectable viral RNA. Paired t-test indicated a significant difference between pre-test and post-test Ct (P < 0.001), which is supported by Monte Carlo test results that revealed statistically significant shifting in viral load categories (P = 0.001, two-sided). As, 85.7% of high-viral-load samples converted to low or moderate content, 46.7% of low or moderate samples were shifted to negative content. This intervention produced a massive effect size (Cohen’s d = 2.422). These results indicate that ultrasound may offer a promising non-pharmacological approach to target any enveloped viruses.