It is common that different crystal facets in metal and metal oxide nanocrystals display different catalytic performances, whereas such phenomena have been rarely documented in metal–organic frameworks (MOFs). Herein, we demonstrate for the first time that a nickel metal–organic layer (MOL) exposing rich (100) crystal facets (Ni‐MOL‐100) shows a much higher photocatalytic CO2‐to‐CO activity than the one exposing rich (010) crystal facets (Ni‐MOL‐010) and its bulky counterpart (bulky Ni‐MOF), with a catalytic activity up to 2.5 and 4.6 times more active than Ni‐MOL‐010 and bulky Ni‐MOF, respectively. Theoretical studies reveal that the two coordinatively unsaturated NiII ions with a close distance of 3.50 Å on the surface of Ni‐MOL‐100 enables synergistic catalysis, leading to more favorable energetics in CO2 reduction than that of Ni‐MOL‐010. Crystal‐facet‐dependent catalytic performance for CO2 reduction has been observed in Ni‐based 2D MOLs. Ni‐MOL‐100 displays much higher catalytic activity than Ni‐MOL‐010, benefiting from the synergistic catalysis between two adjacent Ni sites in Ni‐MOL‐100.