Girl in US city's heading south (4)
I believe the answer is:
lass
'girl' is the definition.
(lass can informally mean a girl)
'in us city's heading south' is the wordplay.
'in' indicates putting letters inside.
'us city's' becomes 'LA's' (abbreviation for Los Angeles).
'heading south' becomes 's' (abbreviation).
'las' enclosing 's' is 'LASS'.
(Other definitions for lass that I've seen before include "Sweet resident of Richmond Hill?" , "Scottish girl" , "Miss" , "Sweetheart" , "Young woman, girl" .)