Mercury (Hg) levels in Ontario top predator fishes have been increasing in recent decades. These increases may be a result of many additive factors, including global climate change. Only recently has research been conducted on how climate change may impact Hg levels in freshwater fishes at large-scales. We examined the relationship between Hg trends and (1) local weather, (2) large-scale climate drivers, and (3) anthropogenic Hg emissions, in native cool water (walleye and northern pike) and warm water (smallmouth bass and largemouth bass) predatory fishes in Ontario, Canada, for historical (1970–1992) and recent (1993–2014) time periods. For each fish species studied, > 25% of Ontario's secondary watersheds shifted from historically declining to recently increasing fish Hg trends, and ≥ 50% of watersheds experienced increasing trends between 1993 and 2014. Recent fish Hg increased at up to 0.20 μg/g/decade; which were significant (p < 0.05) for walleye, northern pike and smallmouth bass. Multiple linear regressions revealed a complex interplay of local weather, large-scale climate drivers, and anthropogenic Hg emissions influencing fish Hg levels. Recent Hg levels for walleye and largemouth bass increased with changes in global climate drivers, while higher precipitation influenced smallmouth bass Hg levels the most. Walleye Hg levels increased during the positive phases of global climate drivers, reflecting the local influence of local temperatures and precipitation indirectly. Differentiating the effects of climate-related parameters and emissions is increasingly crucial to assess how changing multiple environmental stressors may impact health of wildlife and humans consuming fish.