Prior joint injury predisposes an individual to developing post-traumatic osteoarthritis, for which there is presently no disease modifying treatment. In this condition, articular cartilage degenerates due to cell death and matrix breakdown, resulting in tissue with diminished biomechanical function. P188, a nonionic surfactant, and the growth factor IGF-I have been shown to decrease cell death. Additionally, IGF-I is known to have beneficial effects on cartilage matrix. The objective of this study was to determine the efficacy of P188, IGF-I, and their combination following articular cartilage impact injury with two energy levels, (“low”) and (“high”), at and . Bovine articular cartilage with attached underlying bone was impacted at the low or high level. Impact sites were explanted and examined immediately, or cultured for or in serum-free media supplemented with P188 , IGF-I , or their combination. Gross morphology, cell viability, GAG release to the media, and tissue mechanical properties were assessed. Immediately postimpact, high level impacted tissue had significantly increased gross morphology scores, indicating tissue damage, which were maintained over . Gross scores following low impact were initially similar to nonimpacted controls, but, at and , low impact gross scores significantly increased compared to nonimpacted controls. Additionally, at , high impact resulted in increased cell death, and both low and high impacts had increased GAG release compared to nonimpacted controls. Furthermore, high impact caused decreased tissue stiffness at that appeared to worsen over , evident by the percent decrease from nonimpacted controls increasing from 16% to 26%. No treatment type studied mitigated this loss. The combination did not perform better than either individual treatment; however, following low impact at , P188 reduced cell death by 75% compared to no treatment and IGF-I decreased GAG release from the tissue by 49%. In conclusion, high impact resulted in immediate tissue changes that worsened over . Though not causing immediate changes, low impact also resulted in tissue degeneration evident by . No treatment studied was effective at , but by P188 and IGF-I ameliorated established detrimental changes occurring in articular cartilage postimpact. However, further work is needed to optimize treatment strategies to prevent and/or reverse cell death and matrix destruction in a way that maintains tissue mechanical properties, and hence its functionality.