The Mackenzie River Basin has experienced the highest year to year climate variability in the northern hemisphere during the winter months over the last 50 years. Lakes have special interest since they reflect the influence of large-scale atmospheric and oceanic circulation oscillations (Teleconnections). Seasonal and composite lake water level anomalies for the negative and positive phases of North Pacific (NP), Pacific North American (PNA), Pacific Decadal (PDO), Arctic (AO), and El Niño Southern (ENSO) Oscillations, indicate PDO to have the largest influence on the amplitude of lake level anomalies across Mackenzie River Basin during 1950–2008. NP is more influential than ENSO in the southern part of the basin and during winter seasons. The response to the Arctic Oscillation (AO) effect is only recorded at Great Slave Lake during the spring. Squared coherence, the frequency domain equivalent of correlation, was used to evaluate the modes and frequencies of correlations between the above mentioned lake levels and teleconnection indexes. Great Bear Lake levels are sensitive to the variability of all considered teleconnections at the decadal (PDO) and interannual (ENSO, PNA, NP, AO) bands. The North Pacific followed by Pacific North American and Arctic Oscillations are the most influential teleconnections at interannual frequencies for the southern part of the basin. The influence of flow regulation on Great Slave Lake level variability mainly affects the coherence response at the (1.0–1.5) years' period, without an impact on the low-frequency climate signal, as reflected by significant correlations with ENSO at the 10 years' period and North Pacific and Arctic Oscillations at the 6.6 years' period. The Aleutian Low indexes indicate the highest interannual frequency, which is significant in the basin, corresponds to the (1.5–1.6) years' period. Differences in the slopes of Lake Altimetry Heights (LAH) across Great Slave Lake identifies deeper and colder areas as ideal to study interannual climate variability due to their minimal change in gradient through time, as compared to areas with higher gradient variability. Changes in lake level gradients are more related to surface water temperature distribution than wind effects.