Per- and polyfluoroalkyl substances (PFASs) are highly persistent and toxic contaminants, frequently associated with aqueous film-forming foams (AFFFs), a major source of soil and groundwater pollution. Foam fractionation (FF) is often used to concentrate PFASs from AFFFs, producing PFAS-rich foams that pose disposal challenges. Ultrasonic degradation has emerged as a promising remediation strategy, generating extreme cavitation conditions that induce both radical-mediated and pyrolytic breakdown of PFASs. This study evaluates the effect of oxidants—ferric chloride (FeCl₃), sodium persulfate (Na₂S₂O₈), and hydrogen peroxide (H₂O₂)—on the ultrasonic degradation of two model PFASs (PFOA and PFOS), AFFF, and FF. Ultrasound alone achieved notable defluorination in real-world matrices, with 40% and 46% efficiencies for AFFF and FF, respectively. Addition of Na₂S₂O₈ slightly increased AFFF defluorination to 46% but decreased FF defluorination to 44%, while H₂O₂ maintained 40% for AFFF and enhanced FF to 47%. These results indicate that oxidant effects depend on the matrix: components in AFFF can scavenge reactive species, limiting the benefit of added oxidants, whereas FF allows modest enhancement with H₂O₂. In contrast, pure PFAS solutions consistently exhibited improved defluorination with oxidants. This work underscores both the potential of combining ultrasonication with oxidation chemistry and the critical role of matrix effects in designing effective hybrid PFAS remediation strategies.