Vivianne Miedema got the ball rolling with a 10th-minute opener before Little's fine first strike put Arsenal two goals up in their quest to overtake rivals Tottenham and claim first place, albeit on goal difference for now.
Katie McCabe powered in a third goal and Little converted a penalty for her brace at Meadow Park before Leah Williamson rubbed salt in City's wounds with a stoppage-time header.
Earlier, reigning champions Chelsea laid down a marker with a thumping 6-1 victory over previously unbeaten Manchester United.
Fran Kirby opened the scoring inside two minutes with her 50th Super League goal, and Chelsea were three up at half-time.
Pernille Harder produced a brilliant solo run to double the lead before Sam Kerr tapped home a third.
Alessia Russo gave United hope with a deflected shot shortly after half-time but goals from Kerr, Drew Spence and Jessie Fleming made this emphatically Chelsea's day.
Having been stunned by Arsenal in their opening match, this was a performance to show that Emma Hayes' side are firmly back on track.
Tottenham maintained their perfect start with a 1-0 victory over Reading.
They had to wait until the 85th minute to make the breakthrough, Jessica Naz grabbing the goal.
Aston Villa won by the same scoreline at Brighton, with Emily Gielnik producing a fine finish three minutes after the break.
West Ham secured their first win of the season in fine style with a 4-0 victory over Leicester.
Australian debutant Tameka Yallop opened the scoring in the 26th minute, and Claudia Walker added her first goal for the club 12 minutes later.
An unfortunate own goal from Ashleigh Plumptre made it three just before half-time and Yallop netted her second late in the second half.