Europa League holders Atletico Madrid and Serie A title challengers Napoli were upset at home while of the English football teams in action in the second-tier competition, only Liverpool were beaten.
Atletico suffered a shock 2-0 home loss to Russians Rubin Kazan and unfancied Czechs Viktoria Plzen posted an upset 3-0 win at Napoli.
Russian former champions Zenit St Petersburg won 2-0 at home over the five-times European Cup-winning Reds, while Chelsea won 1-0 away at Sparta Prague.
Tottenham Hotspur beat French visitors Lyon 2-1, and Newcastle were held 0-0 at home by Metalist Kharkiv of Ukraine.
In other last 32 ties, Russia's Anzhi Makhachkala also opened up a commanding first-leg advantage by repelling Germans Hanover 3-1.
Three-times European champions Inter Milan beat Champions League dropouts CFR Cluj 2-0 and there were impressive wins for Spanish club Levante, who beat runaway Greek league leaders Olympiakos Piraeus 3-0 at home and Ajax Amsterdam, 2-0 victors against former European champions Steaua Bucharest in the Netherlands.