Как насчет этого:
df1 = pandas.DataFrame(data = {'col1' : [1, 2, 3, 4, 5],
'col2' : [10, 11, 12, 13, 14]})
df2 = pandas.DataFrame(data = {'col1' : [1, 2, 3],
'col2' : [10, 11, 12]})
records_df2 = set([tuple(row) for row in df2.values])
in_df2_mask = np.array([tuple(row) in records_df2 for row in df1.values])
result = df1[~in_df2_mask]