On foot
Centre City is dense enough that it can be usually be easily walked. Certain intersections basically anything along Harbor Drive can feel a little risky with the high volume of cars, but for the most part walking is quite safe, even at night. Just keep in mind that Downtown is fairly large, so if you're planning on hoofing it from Little Italy to PETCO Park, keep in mind it's a long walk.
By car
Downtown is easily accessible and traversed by automobile, but it is one of the very few areas of San Diego where it makes sense to get around by other means. Parking is expensive and can be very hard to find during special events like Padres games at PETCO Park. You can park at the garage at Westfield Horton Plaza for free for up to 3 hours as long as you validate the ticket at the small validation machines inside of the mall.