The negative impacts of invasive Burmese pythons (Python bivittatus) on mammal communities in mainland South Florida are well-documented. However, few studies have examined the ecological effects of Burmese pythons along their southern invasion front in the Florida Keys. The establishment of Burmese pythons in the Keys could be devastating for island mammal communities and their ecosystem functions. We leveraged long-term data from camera trap surveys of endangered Key Largo woodrats (Neotoma floridana smalli) and free-ranging cats (Felis catus), as well as publicly available datasets to create time-dependent occupancy and generalized linear models to explore potential changes in the mammal community associated with increasing prevalence of Burmese pythons on Key Largo. Top occupancy models indicated that detection probabilities of endangered Key Largo cotton mice (Peromyscus gossypinus allapaticola), Key Largo woodrats, and invasive black rats (Rattus rattus) all decreased since the establishment of Burmese pythons in 2016 on North Key Largo, but the detection probability of Virginia opossums (Didelphis virginiana) might have increased. Additionally, top models indicated that increasing python prevalence was associated with high local extinction probabilities for woodrats and black rats. Generalized linear models indicated raccoon (Procyon lotor) and opossum counts decreased locally over time in areas where pythons were present, despite no broad-scale changes in occupancy. These results reveal a complex dynamic wherein Burmese pythons are likely having a stronger effect on rodent communities over mesopredator communities in North Key Largo-presumably due to demographics of a relatively new established python population. This study indicates that the python invasion in Key Largo has started to have ecological impacts. While these findings are cause for concern, evidence does suggest python removals are mitigating effects on certain mammal populations.